Androgen receptor modulators

ABSTRACT

Compounds of structural Formula (I) are modulators of the androgen receptor (AR) in a tissue selective manner These compounds are useful in the enhancement of weakened muscle tone and the treatment of conditions caused by androgen deficiency or which can be ameliorated by androgen administration, including osteoporosis, osteopenia, glucocorticoid-induced osteoporosis, periodontal disease, bone fracture, bone damage following bone reconstructive surgery, sarcopenia, frailty, aging skin, male hypogonadism, postmenopausal symptoms in women, atherosclerosis, hypercholesterolemia, hyperlipidemia, obesity, aplastic anemia and other hematopoietic disorders, inflammatory arthritis and joint repair, HIV-wasting, prostate cancer, benign prostatic hyperplasia (BPH), abdominal adiposity, metabolic syndrome, type II diabetes, cancer cachexia, Alzheimer&#39;s disease, muscular dystrophies, cognitive decline, sexual dysfunction, sleep apnea, depression, premature ovarian failure, and autoimmune disease, alone or in combination with other active agents.

This application is a 371 National Stage Application of PCT/US2005/029592, filed on Aug. 19, 2005, which claims priority from U.S.Provisional Application Appln. No. 60/604,368, filed on Aug. 25, 2004.

FIELD OF THE INVENTION

The present invention relates to 3-4 fused-imidazolyl steroidalderivatives, their synthesis, and their use as androgen receptormodulators. More particularly, the compounds of the present inventionare tissue-selective androgen receptor modulators (SARMs) and arethereby useful for the treatment of conditions caused by androgendeficiency or which can be ameliorated by androgen administration, suchas osteoporosis, periodontal disease, bone fracture, frailty, andsarcopenia. Additionally, the SARMs of the present invention can be usedto treat mental disorders associated with low testosterone, such asdepression, sexual dysfunction, and cognitive decline. SARMs, beingantagonists in specific tissues, are also useful in conditions whereelevated androgen tone or activity causes symptoms, such as benignprostate hyperplasia and sleep apnea.

BACKGROUND OF THE INVENTION

The androgen receptor (AR) belongs to the superfamily of steroid/thyroidhormone nuclear receptors, whose other members include the estrogenreceptor, the progesterone receptor, the glucocorticoid receptor, andthe mineralocorticoid receptor. The AR is expressed in numerous tissuesof the body and is the receptor through which the physiological as wellas the pathophysiological effects of androgens, such as testosterone (T)and dihydrotestosterone (DHT), are mediated. Structurally, the AR iscomposed of three functional domains: the ligand binding domain (LBD),the DNA-binding domain, and amino-terminal domain. A compound that bindsto the AR and mimics the effects of an endogenous AR ligand is referredto as an AR agonist, whereas a compound that inhibits the effects of anendogenous AR ligand is termed an AR antagonist.

Androgen ligand binding to the AR induces a ligand/receptor complex,which, after translocation into the nucleus of the cell, binds toregulatory DNA sequences (referred to as androgen response elements)within the promoter or enhancer regions of the target genes present inthe nucleus. Other proteins termed cofactors are next recruited, whichbind to the receptor leading to gene transcription.

Androgen therapy has been to treat a variety of male disorders such asreproductive disorders and primary or secondary male hypogonadism.Moreover, a number of natural or synthetic AR agonists have beeninvestigated for the treatment of musculoskeletal disorders, such asbone disease, hematopoietic disorders, neuromuscular disease,rheumatological disease, wasting disease, and for hormone replacementtherapy (HRT), such as female androgen deficiency. In addition, ARantagonists, such as flutamide and bicalutamide, are used to treatprostate cancer. It would therefore be useful to have availablecompounds that can activate (“agonize”) the function of the AR in atissue-selective manner that would produce the desired osteo- andmyoanabolic effects of androgens without the negative androgenicproperties, such as virilization and repression of high densitylipoprotein cholesterol (HDL).

The beneficial effects of androgens on bone in postmenopausalosteoporosis were documented in recent studies using combinedtestosterone and estrogen administration [Hofbauer, et al., Eur. J.Edocrinol. 140: 271-286 (1999)]. In a large 2-year, double-blindcomparison study, oral conjugated estrogen (CEE) and methyltestosteronecombinations were demonstrated to be effective in promoting accrual ofbone mass in the spine and hip, while conjugated estrogen therapy aloneprevented bone loss [J. Reprod. Med., 44: 1012-1020 (1999)].

Additionally, there is evidence that hot flushes decrease in womentreated with CEE and methyltestosterone; however, 30% of the treatedwomen suffered from significant increases in acne and facial hair, acomplication of all current androgen pharmacotherapies [Watts, et al.,Obstet. Gynecol., 85: 529-537 (1995)]. It was also found that theaddition of methyltestosterone to CEE decreased HDL levels, as seen inother studies. Thus, the virilizing potential and effects on lipidprofile of current androgen therapies provide a rationale for developingtissue-selective androgen receptor agonists.

Androgens play an important role in bone metabolism in men [Anderson, etal., “Androgen supplementation in eugonadal men withosteoporosis—effects of six months of treatment on bone mineral densityand cardiovascular risk factors,” Bone, 18: 171-177 (1996)]. Even ineugonadal men with osteoporosis, the therapeutic response totestosterone treatment reveals that androgens exert importantosteoanabolic effects. Mean lumbar BMD increased from 0.799 gm/cm2 to0.839 g/cm2, in 5 to 6 months in response to 250 mg of testosteroneester administered intramuscularly. SARMs can thus be used to treatosteoporosis in men.

Androgen deficiency occurs in men with stage D prostate cancer(metastatic) who undergo androgen deprivation therapy (ADT). Endocrineorchiectomy is achieved by long acting GnRH agonists, while androgenreceptor blockade is implemented with AR antagonists. In response tohormonal deprivation, these men suffered from hot flushes, significantbone loss, weakness, and fatigue. In a pilot study of men with stage Dprostate cancer, osteopenia (50% vs. 38%) and osteoporosis (38% vs. 25%)were more common in men who had undergone ADT for greater than one yearthan the patients who did not undergo ADT [Wei, et al., Urology, 54:607-611 (1999)]. Lumbar spine BMD was significantly lower in men who hadundergone ADT. Thus tissue selective AR antagonists in the prostate thatlack antagonistic action in bone and muscle can be useful agents for thetreatment of prostate cancer, either alone or as an adjunct totraditional ADT [See also A. Stoch, et al., J. Clin. Endocrin. Metab.,86: 2787-2791 (2001)].

Tissue-selective AR antagonists can also treat polycystic ovariansyndrome in postmenopausal women. See C. A. Eagleson, et al.,“Polycystic ovarian syndrome: evidence that flutamide restoressensitivity of the gonadotropin-releasing hormone pulse generator toinhibition by estradiol and progesterone,” J. Clin. Endocrinol. Metab.,85: 4047-4052 (2000).

SARMs can also treat certain hematopoietic disorders as androgensstimulate renal hypertrophy and erythropoietin (EPO) production. Priorto the introduction of recombinant human EPO, androgens were employed totreat anemia caused by chronic renal failure. In addition, androgensincrease serum EPO levels in anemic patients with non-severe aplasticanemia and myelodysplastic syndromes. Treatment for anemia will requireselective action such as can be provided by SARMs.

SARMs can also have clinical value as an adjunct to the treatment ofobesity. This approach to lowering body fat is supported by publishedobservations that androgen administration reduced subcutaneous andvisceral fat in obese patients [J. C. Lovejoy, et al., “Oral anabolicsteroid treatment, but not parenteral androgen treatment, decreasesabdominal fat in obese, older men,” Int. J. Obesity, 19: 614-624(1995)], [J. C. Lovejoy, et al., “Exogenous Androgens Influence BodyComposition and Regional Body Fat Distribution in Obese PostmenopausalWomen—A Clinical Research Center Study,” J. Clin. Endocrinol. Metab.,81: 2198-2203 (1996)]. Therefore, SARMs devoid of unwanted androgeniceffects can be beneficial in the treatment of obesity.

Androgen receptor agonists can also have therapeutic value againstmetabolic syndrome (insulin resistance syndrome, syndrome X),particularly in men. Low levels of total and free testosterone and sexhormone-binding globulin (SHEG) in men have been associated with type 2diabetes, visceral obesity, insulin resistance (hyperinsulinemia,dyslipidemia) and metabolic syndrome. D. Laaksonen, et al., DiabetesCare, 27 (5): 1036-1041(2004); see also D. Laaksonen, et al. Euro. J.Endocrin, 149: 601-608 (2003); P. Márin, et al. Int. J. Obesity, 16:991-997 (1992), and P. Márin, et al. Obesity Res., 1(4): 245-251 (1993).

Androgen receptor agonists can also have therapeutic value againstneurodegenerative diseases such as Alzheimer's disease (AD). The abilityof androgens to induce neuroprotection through the androgen receptor wasreported by J. Hammond, et al., “Testosterone-mediated neuroprotectionthrough the androgen receptor in human primary neurons,” J. Neurochem.,77: 1319-1326 (2001). Gouras et al. reported that testosterone reducessecretion of Alzheimer's β-amyloid peptides and can therefore be used inthe treatment of AD [(Proc. Nat. Acad. Sci., 97: 1202-1205 (2000)]. Amechanism via inhibition of hyperphosphorylation of proteins implicatedin the progression AD has also been described [S. Papasozomenos,“Testosterone prevents the heat shock-induced over activation ofglycogen synthase kinase-3β but not of cyclin-dependent kinase 5 andc-Jun NH2-terminal kinase and concomitantly abolisheshyperphosphorylation of τ: Implications for Alzheimer's disease,” Proc.Nat. Acad. Sci., 99: 1140-1145 (2002)].

Androgen receptor agonists can also have a beneficial effect on muscletone and strength. Recent studies have demonstrated that “physiologicandrogen replacement in healthy, hypogonadal men is associated withsignificant gains in fat-free mass, muscle size and maximal voluntarystrength,” [S. Bhasin, et al., J. Endocrin., 170: 27-38 (2001)].

Androgen receptor modulators can be useful in treating decreased libidoin both men and women. Androgen deficiency in men is related todiminished libido. S. Howell et al., Br. J. Cancer, 82: 158-161. Lowandrogen levels contribute to the decline in sexual interest in manywomen during their later reproductive years. S. Davis, J. Clin.Endocrinol. Metab., 84: 1886-1891 (1999). In one study, circulating freetestosterone was positively correlated with sexual desire. Id. Inanother study, women with primary or secondary adrenal insufficiencywere provided physiological DHEA replacement (50 mg/day). Compared withwomen taking placebo, DHEA-administered women showed an increase in thefrequency of sexual thoughts, interest, and satisfaction. W. Arlt, etal., N Engl. J. Med. 341:1013-1020 (1999), see also, K. Miller, J. Clin.Endocrinol. Metab., 86: 2395-2401 (2001).

Additionally, androgen receptor modulators may also be useful intreating cognitive impairment. In a recent study, high-dose oralestrogen either alone or in combination with high-dose oralmethyltestosterone was given to postmenopausal women for a four-monthperiod. Cognitive tests were administered before and after thefour-month hormone treatment. The investigation found that womenreceiving a combination of estrogen (1.25 mg) and methyltestosterone(2.50 mg) maintained a steady level of performance on the BuildingMemory task, but the women receiving estrogen (1.25 mg) alone exhibiteddecreased performance. A. Wisniewski, Horm. Res. 58:150-155 (2002).

SUMMARY OF THE INVENTION

The present invention relates to compounds of structural formula I:

or a pharmaceutically acceptable salt or stereoisomer thereof, theiruses, and pharmaceutical compositions.

These compounds are effective as androgen receptor agonists and areparticularly effective as SARMs. They are therefore useful for thetreatment of conditions caused by androgen deficiency or which can beameliorated by androgen administration.

The present invention also relates to pharmaceutical compositionscomprising the compounds of the present invention and a pharmaceuticallyacceptable carrier.

In this invention, we have identified compounds that function as SARMsusing a series of in vitro cell-assays that profile ligand mediatedactivation of AR, such as (i) N—C interaction, (ii) transcriptionalrepression, and (iii) transcriptional activation. SARM compounds in thisinvention, identified with the methods listed above, exhibit tissueselective AR agonism in vivo, i.e. agonism in bone (stimulation of boneformation in a rodent model of osteoporosis) and antagonism in prostate(minimal effects on prostate growth in castrated rodents and antagonismof prostate growth induced by AR agonists).

The compounds of the present invention identified as SARMs are useful totreat diseases or conditions caused by androgen deficiency which can beameliorated by androgen administration. Such compounds are ideal for thetreatment of osteoporosis in women and men as a monotherapy or incombination with inhibitors of bone resorption, such as bisphosphonates,estrogens, SERMs, cathepsin K inhibitors, αvβ3 integrin receptorantagonists, calcitonin, and proton pump inhibitors. They can also beused with agents that stimulate bone formation, such as parathyroidhormone or analogs thereof. The SARM compounds of the present inventioncan also be employed for treatment of prostate disease, such as prostatecancer and benign prostatic hyperplasia (BPH). Moreover, compounds ofthis invention exhibit minimal effects on skin (acne and facial hairgrowth) and can be useful for treatment of hirsutism. Additionally,compounds of this invention can stimulate muscle growth and can beuseful for treatment of sarcopenia and frailty. They can be employed toreduce visceral fat in the treatment of obesity. Moreover, compounds ofthis invention can exhibit androgen agonism in the central nervoussystem and can be useful to treat vasomotor symptoms (hot flush) and toincrease energy and libido. They can be used in the treatment ofAlzheimer's disease.

The compounds of the present invention can also be used in the treatmentof prostate cancer, either alone or as an adjunct to GNRHagonist/antagonist therapy, for their ability to restore bone, or as areplacement for antiandrogen therapy because of their ability toantagonize androgen in the prostate, and minimize bone depletion.Further, the compounds of the present invention can be used for theirability to restore bone in the treatment of pancreatic cancer as anadjunct to treatment with antiandrogen, or as monotherapy for theirantiandrogenic properties, offering the advantage over traditionalantiandrogens of being bone-sparing. Additionally, compounds of thisinvention can increase the number of blood cells, such as red bloodcells and platelets, and can be useful for the treatment ofhematopoietic disorders, such as aplastic anemia. Thus, consideringtheir tissue selective androgen receptor agonism listed above, thecompounds of this invention are ideal for hormone replacement therapy inhypogonadic (androgen deficient) men.

This invention is also concerned with safely and specifically treating amale subject with abdominal adiposity, metabolic syndrome (also known asthe ‘insulin resistance syndrome’, and ‘Syndrome X’), and type IIdiabetes.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to compounds that are useful as androgenreceptor modulators, in particular, as selective androgen receptormodulators (SARMs). Compounds of the present invention are described bystructural formula I:

or an enantiomer or a pharmaceutically acceptable salt thereof; wherein

-   a-b represents CH═CH or CH₂CH₂;-   d is 0 or 1;-   R¹ is selected from hydrogen, C₁₋₄ alkyl, wherein said C₁₋₄ alkyl is    optionally substituted with one or more substituents independently    selected from halogen, hydroxy, C₁₋₄ alkoxy, and C₁₋₄ alkylamino,    and-   R² is chosen from    -   hydrogen,    -   hydroxy C₀₋₁₀alkyl,    -   perfluoroC₁₋₆alkyl,    -   perfluoroC₁₋₆alkoxy,    -   C₁₋₁₀ alkyl,    -   C₂₋₁₀ alkenyl,    -   C₂₋₁₀ alkynyl,    -   aryl C₀₋₁₀ alkyl,    -   C₃₋₈ cycloalkyl C₀₋₁₀ alkyl,    -   C₃₋₈ heterocyclyl C₀₋₁₀ alkyl,    -   (C₀₋₁₀ alkyl)₁₋₂aminocarbonyloxy C₀₋₁₀ alkyl,    -   (aryl C₀₋₁₀ alkyl)₁₋₂aminocarbonyloxy C₀₋₁₀ alkyl,    -   (C₃₋₈ cycloalkyl C₀₋₁₀ alkyl)₁₋₂aminocarbonyloxy C₀₋₁₀ alkyl,    -   (C₃₋₈ heterocyclyl C₀₋₁₀ alkyl)₁₋₂aminocarbonyloxy C₀₋₁₀ alkyl,    -   (C₀₋₁₀ alkyl)₁₋₂aminocarbonylamino C₁₋₁₀ alkyl,    -   (aryl C₀₋₁₀ alkyl)₁₋₂aminocarbonylamino C₁₋₁₀ alkyl,    -   (C₃₋₈ cycloalkyl C₀₋₁₀ alkyl)₁₋₂aminocarbonylamino C₁₋₁₀ alkyl,    -   (C₃₋₈ heterocyclyl C₀₋₁₀ alkyl)₁₋₂aminocarbonylamino C₁₋₁₀        alkyl,    -   (C₀₋₁₀ alkyl)₁₋₂aminocarbonyl C₀₋₁₀ alkyl,    -   (aryl C₀₋₁₀ alkyl)₁₋₂aminocarbonyl C₀₋₁₀ alkyl,    -   C₃₋₈ cycloalkyl C₀₋₁₀ alkyl aminocarbonyl C₀₋₁₀ alkyl,    -   C₃₋₈ heterocyclyl C₀₋₁₀ alkyl aminocarbonyl C₀₋₁₀ alkyl,    -   C₀₋₁₀ alkyl carbonylamino C₀₋₁₀ alkyl,    -   C₃₋₈ cycloalkyl C₀₋₁₀ alkyl carbonylamino C₁₋₁₀ alkyl,    -   C₃₋₈ heterocyclyl C₀₋₁₀ alkyl carbonylamino C₁₋₁₀ alkyl,    -   aryl C₀₋₁₀ alkyl carbonylamino C₁₋₁₀ alkyl,    -   C₀₋₁₀ alkyloxy carbonylamino C₁₋₁₀ alkyl,    -   C₃₋₈ cycloalkyl C₀₋₁₀ alkyloxy carbonylamino C₁₋₁₀ alkyl,    -   C₃₋₈ heterocyclyl C₀₋₁₀ alkyloxy carbonylamino C₁₋₁₀ alkyl,    -   aryl C₀₋₁₀ alkyloxy carbonylamino C₁₋₁₀ alkyl,    -   C₀₋₁₀ alkyloxy carbonyloxy C₀₋₁₀ alkyl,    -   C₃₋₈ cycloalkyl C₀₋₁₀ alkyloxy carbonyloxy C₀₋₁₀ alkyl,    -   C₃₋₈ heterocyclyl C₀₋₁₀ alkyloxy carbonyloxy C₀₋₁₀ alkyl,    -   aryl C₀₋₁₀ alkyloxy carbonyloxy C₀₋₁₀ alkyl,    -   C₁₋₁₀ alkoxy (carbonyl)₀₋₁C₀₋₁₀ alkyl,    -   C₁₋₁₀alkyloxy C₀₋₁₀alkyl,    -   aryloxy C₀₋₁₀ alkyl,    -   C₃₋₈ cycloalkyloxy C₀₋₁₀ alkyl,    -   C₃₋₈ heterocyclyloxy C₀₋₁₀ alkyl,    -   C₃₋₈ heterocyclylC₀₋₁₀alkyloxy C₀₋₁₀ alkyl, and    -   C₁₋₁₀ alkylcarbonyloxy C₀₋₁₀ alkyl;-   wherein in R², said aryl is selected from phenyl, naphthyl, indanyl,    and tetrahydronapthyl, and said heterocyclyl is selected from    azabenzimidazolyl, benzimidazolyl, benzofuranyl, benzothiophenyl,    benzoxazolyl, benzothiazolyl, benzodihydrofuranyl,    1,3-benzodioxolyl, 2,3-dihydro-1,4-benzodioxinyl, imidazolyl,    indanyl, indolyl, indazoyl, isoquinolyl, isothiazolyl, isoxazolyl,    quinolyl, furanyl, thienyl, oxazolyl, thiazolyl, pyrazolyl,    pyrrolyl, pyridyl, pyrimidyl, pyrazinyl, thiadiazolyl, oxadiazolyl,    triazolyl, imidizopyridinyl, and tetrazolyl; and-   further wherein in R² is optionally substituted with one or more    groups, R³, chosen from halogen, aryl, C₁₋₈ alkyl, C₃₋₈ cycloalkyl,    C₃₋₈ cycloheteroalkyl, aryl-C₁₋₆ alkyl, amino-C₀₋₆ alkyl, C₁₋₆    alkylamino-C₀₋₆ alkyl, (C₁₋₆ alkyl)₂amino-C₀₋₆ alkyl, aryl-C₀₋₆    alkylamino-C₀₋₆ alkyl, (aryl-C₀₋₆ alkyl)₂amino-C₀₋₆ alkyl, C₁₋₆    alkylthio, aryl-C₀₋₆ alkylthio, C₁₋₆ alkylsulfinyl, aryl-C₀₋₆    alkylsulfinyl, C₁₋₆ alkylsulfonyl, aryl-C₀₋₆ alkylsulfonyl, C₁₋₆    alkoxy-C₀₋₆ alkyl, aryl-C₀₋₆ alkoxy-C₀₋₆ alkyl, hydroxycarbonyl-C₀₋₆    alkyl, C₁₋₆ alkoxycarbonyl-C₀₋₆ alkyl, aryl-C₀₋₆ alkoxycarbonyl-C₀₋₆    alkyl, hydroxycarbonyl-C₁₋₆ alkyloxy, hydroxy-C₀₋₆ alkyl, cyano,    nitro, perfluoro-C₁₋₄ alkyl, perfluoro-C₁₋₄ alkoxy, C₁₋₆    alkylcarbonyloxy, aryl-C₀₋₆alkylcarbonyloxy, C₁₋₆alkylcarbonylamino,    aryl-C₀₋₆ alkylcarbonylamino, C₁₋₆ alkylsulfonylamino, aryl-C₀₋₆    alkylsulfonylamino, C₁₋₆ alkoxycarbonylamino, aryl-C₀₋₆    alkoxycarbonylamino, C₁₋₆ alkylaminocarbonylamino, aryl-C₀₋₆    alkylaminocarbonylamino, (C₁₋₆ alkyl)₂ aminocarbonylamino,    (aryl-C₀₋₆ alkyl)₂ aminocarbonylamino, (C₁₋₆ alkyl)₂    aminocarbonyloxy, and (aryl-C₀₋₆ alkyl)₂ aminocarbonyloxy; and-   wherein R³ is optionally substituted with one or more groups chosen    from: OH, C₁₋₆ alkoxy, halogen, CO₂H, CN, O(C═O)C₁₋₆ alkyl, NO₂,    trifluoromethoxy, trifluoroethoxy, —O(_(d))(C₁₋₁₀)perfluoroalkyl,    and NH₂.

Illustrative but nonlimiting examples of compounds of the invention arethe following:

-   N-(2,6-dichloropyridin-3-yl)-(5aR,5by, 7aS, 8R, 10aS,    10bS)-5b,6,7,7a,8,9,10,10a,10b,11,12,12a-dodecahydro-5aH-imidazo[1,2-a]indeno[5,4-f]quinoline-8-carboxamide;-   N-(2-cyano-3-fluorophenyl)-(5aR,5bS, 7aS, 8R, 10aS,    10bS)-5b,6,7,7a,8,9,10,10a,10b,11,12,12a-dodecahydro-5aH-imidazo[1,2-a]indeno[5,4-f]quinoline-8-carboxamide;-   N-(2-cyano-3-chlorophenyl)-(5aR,5bS, 7aS, 8R, 10aS,    10bS)-5b,6,7,7a,8,9,10,10a,10b,11,12,12a-dodecahydro-5aH-imidazo[1,2-a]indeno[5,4-f]quinoline-8-carboxamide;-   N-(2-cyano-4-chlorophenyl)-(5aR,5bS, 7aS, 8R, 10aS,    10bS)-5b,6,7,7a,8,9,10,10a,10b,11,12,12a-dodecahydro-5aH-imidazo[1,2-a]indeno[5,4-f]quinoline-8-carboxamide;-   N-(2-cyano-3-methylphenyl)-(5aR,5bS, 7aS, 8R, 10aS,    10bS)-5b,6,7,7a,8,9,10,10a,10b,11,12,12a-dodecahydro-5aH-imidazo[1,2-a]indeno[5,4-f]quinoline-8-carboxamide;-   N-(2-chlorophenyl)-(5aR,5bS, 7aS, 8R, 10aS,    10bS)-5b,6,7,7a,8,9,10,10a,10b,11,12,12a-dodecahydro-5aH-imidazo[1,2-a]indeno[5,4-f]quinoline-8-carboxamnide;-   N-(2-cyano-5-methylphenyl)-(5aR,5bS, 7aS, 8R, 10aS,    10bS)-5b,6,7,7a,8,9,10,10a,10b,11,12,12a-dodecahydro-5aH-imidazo[1,2-a]indeno[5,4-f]quinoline-8-carboxamide;-   N-(3-chlorophenyl)-(5aR,5bS, 7aS, 8R, 10aS,    10bS)-5b,6,7,7a,8,9,10,10a,10b,11,12,12a-dodecahydro-5aH-imidazo[1,2-a]indeno[5,4-f]quinoline-8-carboxamide;-   N-(2,6-dichlorophenyl)-(5aR,5bS, 7aS, 8R, 10aS,    10bS)-5b,6,7,7a,8,9,10,10a,10b,11,12,12a-dodecahydro-5aH-imidazo[1,2-a]indeno[5,4-f]quinoline-8-carboxamide;-   N-(2-fluorophenyl)-(5aR,5bS, 7aS, 8R, 10aS,    10bS)-5b,6,7,7a,8,9,10,10a,10b,11,12,12a-dodecahydro-5aH-imidazo[1,2-a]indeno[5,4-f]quinoline-8-carboxamide-   N-(3-fluorophenyl)-(5aR,5bS, 7aS, 8R, 10aS,    10bS)-5b,6,7,7a,8,9,10,10a,10b,    11,12,12a-dodecahydro-5aH-imidazo[1,2-a]indeno[5,4-f]quinoline-8-carboxamide;-   N-Benzyl-(5aR,5bS, 7aS, 8R, 10aS,    10bS)-5b,6,7,7a,8,9,10,10a,10b,11,12,12a-dodecahydro-5aH-imidazo[1,2-a]indeno[5,4-f]quinoline-8-carboxamide;-   N-(1-phenylethyl)-(5aR,5bS, 7aS, 8R, 10aS, 10bS)-5b,6,7,7a,8,9,    10,10a,10b,11,12,12a-dodecahydro-5aH-imidazo[1,2-a]indeno[5,4-f]quinoline-8-carboxamide;-   N-[(1-(2-chlorophenyl)ethyl]-(5aR,5bS, 7aS, 8R, 10aS,    10bS)-5b,6,7,7a,8,9,10,10a,10b,11,12,12a-dodecahydro-5a-H-imidazo[1,2-a]indeno[5,4-f]quinoline-8-carboxamide;-   N-[(1-(3-chlorophenyl)ethyl]-(5aR,5bS, 7aS, 8R, 10aS,    10bS)-5b,6,7,7a,8,9,10,10a,10b,11,12,12a-dodecahydro-5aH-imidazo[1,2-a]indeno[5,4-f]quinoline-8-carboxamide;-   N-[(1-(2,6-dichlorophenyl)ethyl]-(5aR,5bS, 7aS, 8R, 10aS,    10bS)-5b,6,7,7a,8,9,10,10a,10b,11,12,12a-dodecahydro-5aH-imidazo[1,2-a]indeno[5,4-f]quinoline-8-carboxamide;-   N-[1-(1,3-benzodioxol-5-yl)ethyl]-(5aR,5bS, 7aS, 8R, 10aS,    10bS)-5b,6,7,7a,8,9,10,10a,10b,11,12,12a-dodecahydro-5aH-imidazo[1,2-a]indeno[5,4-f]quinoline-8-carboxamide;-   N-[(1H-imidazol-2-yl)methyl]-(5aR,5bS, 7aS, 8R, 10aS,    10bS)-5b,6,7,7a,8,9,10,10a,10b,    11,12,12a-dodecahydro-5aH-imidazo[1,2-a]indeno[5,4-f]quinoline-8-carboxamide;-   N-[(4-methyl-1H-imidazol-2-yl)methyl]-((5aR,5bS, 7aS, 8R, 10aS,    10bS)-5b,6,7,7a,,9,10,10a,10b,    11,12,12a-dodecahydro-5aH-imidazo[1,2-a]indeno[5,4-f]quinoline-8-carboxamide;-   N-(1H-benzimidazol-2-ylmethyl)-(5aR,5Bs, 7aS, 8R, 10aS,    10bS)-5b,6,7,7a,8,9,10,10a,10b,11,12,12a-dodecahydro-5aH-imidazo[1,2-a]indeno[5,4-f]quinoline-8-carboxamide;-   N-(5-methoxy-1H-benzimidazol-2-ylmethyl)-((5aR,5bS, 7aS, 8R, 10aS,    10bS) 5b,6,7,7a,8,9,10,    10a,10b,11,12,12a-dodecahydro-5a-H-imidazo[1,2-a]indeno[5,4-f]quinoline-8-carboxamide;-   N-(2-fluorobenzyl)-(5aR,5bS, 7aS, 8R, 10aS,    10bS)-5b,6,7,7a,8,9,10,10a,10b,11,12,12a-dodecahydro-5aH-imidazo[1,2-a]indeno[5,4-j]quinoline-8-carboxamide;-   N-(3-fluorobenzyl)-(5aR,5bS, 7aS, 8R, 10aS, 10bS)-5b,6,7,7a,8,9,    10,10a,10b,11,12,12a-dodecahydro-5aH-imidazo[1,2-a]indeno[5,4-f]quinoline-8-carboxamide;-   N-(4-fluorobenzyl)-(5aR,5bS, 7aS, 8R, 10aS,    10bS)-5b,6,7,7a,8,9,10,10a,10b,11,12,12a-dodecahydro-5aH-imidazo[1,2-a]indeno[5,4-f]quinoline-8-carboxamide;-   N-(2,6-difluorobenzyl)-(5aR,5bS, 7aS, 8R, 10aS, 10bS)-5b,6,7,7a,8,9,    10,    10a,10b,11,12,12a-dodecahydro-5aH-imidazo[1,2-a]indeno[5,4-f]quinoline-8-carboxamide;-   N-(pyridin-2-ylmethyl)-(5aR,5bS, 7aS, 8R, 10aS,    10bS)-5b,6,7,7a,8,9,10,10a,10b,11,12,12a-dodecahydro-5aH-imidazo[1,2-a]indeno[5,4-f]quinoline-8-carboxamide;-   N-(pyridin-3-ylmethyl)-(5aR,5bS, 7aS, 8R, 10aS,    10bS)-5b,6,7,7a,8,9,10,10a,10b,11,12,12a-dodecahydro-5aH-imidazo[1,2-a]indeno[5,4-f]quinoline-8-carboxamide;-   N-(pyridin-4-ylmethyl)-(5aR,5bS, 7aS, 8R, 10aS,    10bS)-5b,6,7,7a,8,9,10,10a,10b,11,12,12a-dodecahydro-5aH-imidazo[1,2-a]indeno[5,4-f]quinoline-8-carboxamide;-   N-(2-methylbenzyl)-(5aR,5bS, 7aS, 8R, 10aS,    10bS)-5b,6,7,7a,8,9,10,10a,10b,11,12,12a-dodecahydro-5aH-imidazo[1,2-a]indeno[5,4-f]quinoline-8-carboxamide;-   N-(3-methylbenzyl)-(5aR,5bS, 7aS, 8R, 10aS, 10bS)-5b,6,7,7a,8,9,10,    10a,10b,11,12,12a-dodecahydro-5aH-imidazo[1,2-a]indeno[5,4-f]quinoline-8-carboxamide;-   N-(4-methylbenzyl)-(5aR,5bS, 7aS, 8R, 10aS,    10bS)-5b,6,7,7a,8,9,10,10a,10b,11,12,12a-dodecahydro-5aH-imidazo[1,2-a]indeno[5,4-f]quinoline-8-carboxamide;-   N-(1R,1-phenylpropyl)-(5aR,5bS, 7aS, 8R, 10aS,    10bS)-5b,6,7,7a,8,9,10,10a,10b,11,12,12a-dodecahydro-5aH-imidazo[1,2-a]indeno[5,4-f]quinoline-8-carboxamide;-   N-(1S, 1-phenylpropyl)-(5aR,5bS, 7aS, 8R, 10aS,    10bS)-5b,6,7,7a,8,9,10,10a,10b,11,12,12a-dodecahydro-5aH-imidazo[1,2-a]indeno[5,4-f]quinoline-8-carboxamide;-   N-(1H-imidazo[4,5-b]pyridin-2-ylmethyl)-(5aR,5bS, 7aS, 8R, 10aS,    10bS)-5b,6,7,7a,8,9,10,10a,10b,11,    12,12a-dodecahydro-5aH-imidazo[1,2-a]indeno[5,4-f]quinoline-8-carboxamide;-   N-[(4-methylthio-1H-imidazol-2-yl)methyl]-(5aR,5bS, 7aS, 8R, 10aS,    10bS)-5b,6,7,7a,8,9,10,10a,    10b,11,12,12a-dodecahydro-5aH-imidazo[1,2-a]indeno[5,4-f]quinoline-8-carboxamide;-   N-(2-chloro-4-cyanophenyl)-(5aR,5bS, 7aS, 8R, 10aS,    10bS)-5b,6,7,7a,8,9,10,10a,10b,11,12,12a-dodecahydro-5aH-imidazo[1,2-a]indeno[5,4-f]quinoline-8-carboxamide;-   N-(3,5-dichloropyridin-2-yl)-(5aR,5bS, 7aS, 8R, 10aS,    10bS)-5b,6,7,7a,8,9,10,10a,10b,11,12,12a-dodecahydro-5aH-imidazo[1,2-a]indeno[5,4-f]quinoline-8-carboxamide;-   N-(4-chloropyridin-3-yl)-(5aR,5bS, 7aS, 8R, 10aS,    10bS)-5b,6,7,7a,8,9,10,10a,10b,11,12,12a-dodecahydro-5aH-imidazo[1,2-a]indeno[5,4-f]quinoline-8-carboxamide;-   N-(2-chloropyridin-3-yl)-(5aR,5bS, 7aS, 8R, 10aS,    10bS)-5b,6,7,7a,8,9,10,10a,10b,11,12,12a-dodecahydro-5aH-imidazo[1,2-a]indeno[5,4-f]quinoline-8-carboxamide;-   N-(2-chloropyridin-5-yl)-(5aR,5bS, 7aS, 8R, 10aS,    10bS)-5b,6,7,7a,8,9,10,10a,10b,11,12,12a-dodecahydro-5aH-imidazo[1,2-a]indeno[5,4-f]quinoline-8-carboxamide;-   N-[1-(pyridin-2-yl)ethyl]-(5aR,5bS, 7aS, 8R, 10aS,    10bS)-5b,6,7,7a,8,9,10,10a,10b,11,12,12a-dodecahydro-5aH-imidazo[1,2-a]indeno[5,4-f]quinoline-8-carboxamide;-   N-[1-(pyridin-3-yl)ethyl]-(5aR,5bS, 7aS, 8R, 10aS,    10bS)-5b,6,7,7a,8,9,10,10a,10b,11,12,12a-dodecahydro-5aH-imidazo[1,2-a]indeno[5,4-f]quinoline-8-carboxamide;-   N-[1-(pyridin-4-yl)ethyl]-(5aR,5bS, 7aS, 8R, 10aS,    10bS)-5b,6,7,7a,8,9,10,10a,10b,11,12,12a-dodecahydro-5aH-imidazo[1,2-a]indeno[5,4-f]quinoline-8-carboxamide;-   N-(primidin-4-yl)-(5aR,5bS, 7aS, 8R, 10aS,    10bS)-5b,6,7,7a,8,9,10,10a,10b,11,12,12a-dodecahydro-5aH-imidazo[1,2-a]indeno[5,4-f]quinoline-8-carboxamide;-   N-(5-cyanoprimidin-4-yl)-(5aR,5bS, 7aS, 8R, 10aS,    10bS)-5b,6,7,7a,8,9,10,10a,10b,11,12,12a-dodecahydro-5aH-imidazo[1,2-a]indeno[5,4-f]quinoline-8-carboxamide;-   Methyl 2-{[(5aR,5bS, 7aS, 8R, 10aS,    10bS)-5,5a,5b,6,7,7a,8,9,10,10a,10b,11,12,12a-tetradecahydro-4H-imidazo[1,2-a]indeno[5,4-f]quinolin-8-ylcarbonyl]amino}butanoate;-   N-[(1S)-1-(aminocarbonyl)propyl]-(5aR,5bS, 7aS, 8R, 10aS,    10bS)-5b,6,7,7a,8,9,10,10a,10b,11,12,12a-dodecahydro-5aH-imidazo[1,2-a]indeno[5,4-f]quinoline-8-carboxamide;-   N-[(1S)-1-(methylaminocarbonyl)propyl](5aR,5bS, 7aS, 8R, 10aS,    10bS)-5b,6,7,7a,8,9,10,10a,10b,    11,12,12a-dodecahydro-5a-H-imidazo[1,2-a]indeno[5,4-f]quinoline-8-carboxamide;-   N-[(1S)-1-(dimethylaminocarbonyl)propyl](5aR,5bS, 7aS, 8R, 10aS,    10bS)-5b,6,7,7a,8,9,10,10a,10b,    11,12,12a-dodecahydro-5aH-imidazo[1,2-a]indeno[5,4-f]quinoline-8-carboxamide;-   N-(2,2,2-trifluoroethyl)-(5aR,5bS, 7aS, 8R, 10aS,    10bS)-5b,6,7,7a,8,9,10,10a,10b,11,12,12a-dodecahydro-5aH-imidazo[1,2-a]indeno[5,4-f]quinoline-8-carboxamide;-   N-(3,3,3-trifluoropropyl)-(5aR,5bS, 7aS, 8R, 10aS,    10bS)-5b,6,7,7a,8,9,10,10a,10b,11,12,12a-dodecahydro-5aH-imidazo[1,2-a]indeno[5,4-f]quinoline-8-carboxamide;-   N-[4-(cyanomethyl)phenyl]-(5aR,5bS, 7aS, 8R, 10aS,    10bS)-5b,6,7,7a,8,9,10,10a,10b,11,12,12a-dodecahydro-5aH-imidazo[1,2-a]indeno[5,4-f]quinoline-8-carboxamide;-   Methyl 4-{[(5aR,5bS, 7aS, 8R, 10aS,    10bS)-5b,6,7,7a,8,9,10,10a,10b,11,12,12a-dodecahydro-5aH-imidazo[1,2-a]indeno[5,4-f]quinolin-8-ylcarbonyl]amino}benzoate;-   N-[4-(aminocarbonyl)phenyl]-(5aR,5bS, 7aS, 8R, 10aS,    10bS)-5b,6,7,7a,8,9,10,10a,10b,11,12,12a-dodecahydro-5aH-imidazo[1,2-a]indeno[5,4-f]quinoline-8-carboxamide;-   (5aR,5bS, 7aS, 8R, 10aS,    10bS)-N-[4-(1,2,3-thiadiazol-4-yl)phenyl]-5b,6,7,7a,8,9,10,10a,10b,11,12,12a-dodecahydro-5aH-imidazo[1,2-a]indeno[5,4-f]quinoline-8-carboxamide;-   (5aR,5bS, 7aS, 8R, 10aS, 10bS)-N-(1H-imidazol-6-yl)-5b,6,7,7a,8,9,    10,10a,10b,11,12,12a-dodecahydro-5aH-imidazo[1,2-a]indeno[5,4-f]quinoline-8-carboxamide;-   N-(2,6-dichlorophenyl)-(5aR,5bS, 7aS, 8R, 10aS,    10bS)-5,5a,5b6,7,7a,8,9,10,10a,10b,11,12,12a-tetradecahydro-4H-imidazo[1,2-a]indeno[5,4-f]quinoline-8-carboxamide;-   N-(2-cyanophenyl)-(5aR,5bS, 7aS, 8R, 10aS,    10bS)-5,5a,5b6,7,7a,8,9,10,10a,10b,11,12,12a-tetradecahydro-4H-imidazo[1,2-a]indeno[5,4-f]quinoline-8-carboxamide;-   N-(2-methyl-4-cyanophenyl)-(5aR,5bS, 7aS, 8R, 10aS,    10bS)-5,5a,5b6,7,7a,8,9,10,10a,10b,11,12,12a-tetradecahydro-4H-imidazo[1,2-a]indeno[5,4-f]quinoline-8-carboxamide;-   N-benzyl-(5aR,5bS, 7aS, 8R, 10aS,    10bS)-5,5a,5b6,7,7a,8,9,10,10a,10b,11,12,12a-tetradecahydro-4H-imidazo[1,2-a]indeno[5,4-f]quinoline-8-carboxamide;-   N-(3-chlorobenzyl)-(5aR,5bS, 7aS, 8R, 10aS,    10bS)-5,5a,5b6,7,7a,8,9,10,10a,10b,11,12,12a-tetradecahydro-4H-imidazo[1,2-a]indeno[5,4-f]quinoline-8-carboxamide;-   N-(2,6-dichlorobenzyl)-(5aR,5bS, 7aS, 8R, 10aS,    10bS)-5,5a,5b6,7,7a,8,9,10,10a,10b,11,12,12a-tetradecahydro-4H-imidazo[1,2-a]indeno[5,4-f]quinoline-8-carboxamide;-   N-(2-fluorobenzyl)-(5aR,5bS, 7aS, 8R, 10aS,    10bS)-5,5a,5b6,7,7a,8,9,10,10a,10b,11,12,12a-tetradecahydro-4H-imidazo[1,2-a]indeno[5,4-f]quinoline-8-carboxamide;-   N-(3-fluorobenzyl)-(5aR,5bS, 7aS, 8R, 10aS, 10bS)-5,5a,5b6,7,7a,8,9,    10,10a,10b,11,12,12a-tetradecahydro-4H-imidazo[1,2-a]indeno[5,4-f]quinoline-8-carboxamide;-   N-(2,6-difluorobenzyl)-(5aR,5bS, 7aS, 8R, 10aS,    10bS)-5,5a,5b6,7,7a,8,9,10,10a,10b,11,12,12a-tetradecahydro-4H-imidazo[1,2-a]indeno[5,4-f]quinoline-8-carboxamide;-   N-(pyridin-2-ylmethyl)-(5aR,5bS, 7aS, 8R, 10aS,    10bS)-5,5a,5b6,7,7a,8,9,10,10a,10b,11,12,12a-tetradecahydro-4H-imidazo[1,2-a]indeno[5,4-f]quinoline-8-carboxamide;-   N-(2-methylbenzyl)-(5aR,5bS, 7aS, 8R, 10aS,    10bS)-5,5a,5b6,7,7a,8,9,10,10a,10b,11,12,12a-tetradecahydro-4H-imidazo[1,2-a]indeno[5,4-f]quinoline-8-carboxamide;-   N-(3-methylbenzyl)-(5aR,5bS, 7aS, 8R, 10aS,    10bS)-5,5a,5b6,7,7a,8,9,10,10a,10b,11,12,12a-tetradecahydro-4H-imidazo[1,2-a]indeno[5,4-f]quinoline-8-carboxamide;-   N-(4-methylbenzyl)-(5aR,5bS, 7aS, 8R, 10aS,    10bS)-5,5a,5b6,7,7a,8,9,10,10a,10b,11,12,12a-tetradecahydro-4H-imidazo[1,2-a]indeno[5,4-f]quinoline-8-carboxamide;-   N-[(1R)-1-phenylethyl)]-(5aR,5bS, 7aS, 8R, 10aS,    10bS)-5,5a,5b6,7,7a,8,9,10,10a,10b,11,12,12a-tetradecahydro-4H-imidazo[1,2-a]indeno[5,4-f]quinoline-8-carboxamide;-   N-(1H-benzimidazol-2-ylmethyl)-(5aR,5bS, 7aS, 8R, 10aS,    10bS)-5,5a,5b6,7,7a,8,9,10,10a,10b,    11,12,12a-tetradecahydro-4H-imidazo[1,2-a]indeno[5,4-f]quinoline-8-carboxamide;-   N-(1H-imidazo[4,5-b]pyridin-2-ylmethyl)-(5aR,5bS, 7aS, 8R, 10aS,    10bS)-5,5a,5b6,7,7a,8,9,10,    10a,10b,11,12,12a-tetradecahydro-4H-imidazo[1,2-a]indeno[5,4-f]quinoline-8-carboxamide;-   N-[(4-phenyl-1H-imidazol-2-yl)methyl]-(5aR,5bS, 7aS, 8R, 10aS,    10bS)-5,5a,5b6,7,7a,8,9,10,10a,10b,    11,12,12a-tetradecahydro-4H-imidazo[1,2-a]indeno[5,4-f]quinoline-8-carboxamide;-   N-[(5-chloro-1H-benzoimidazol-2-yl)methyl]-(5aR,5bS, 7aS, 8R, 10aS,    10bS)-5,5a,5b6,7,7a,8,9,10,10a,    10b,11,12,12a-tetradecahydro-4H-imidazo[1,2-a]indeno[5,4-f]quinoline-8-carboxamide;-   N-[(5-methoxy-1H-benzoimidazol-2-yl)methyl]-(5aR,5bS, 7aS, 8R, 10aS,    10bS)-5,5a,5b6,7,7a,8,9,    10,10a,10b,11,12,12a-tetradecahydro-4H-imidazo[1,2-a]indeno[5,4-f]quinoline-8-carboxamide;-   pharmaceutically acceptable salts or stereoisomers thereof.

The compounds of the present invention can have asymmetric centers,chiral axes, and chiral planes (as described in: E. L. Eliel and S. H.Wilen, Stereochemistry of Carbon Compounds, John Wiley & Sons, New York,1994, pages 1119-1190), and occur as racemates, racemic mixtures, and asindividual diastereomers, with all possible isomers and mixturesthereof, including optical isomers, being included in the presentinvention.

The term “alkyl” shall mean straight or branched chain alkanes of one toten total carbon atoms, or any number within this range (i.e., methyl,ethyl, 1-propyl, 2-propyl, n-butyl, s-butyl, t-butyl, etc.). The term“C₀ alkyl” (as in “C₀₋₈ alkylaryl”) shall refer to the absence of analkyl group.

The term “alkenyl” shall mean straight or branched chain alkenes of twoto ten total carbon atoms, or any number within this range.

The term “alkynyl” refers to a hydrocarbon radical straight, branched orcyclic, containing from 2 to 10 carbon atoms and at least one carbon tocarbon triple bond. Up to three carbon-carbon triple bonds can bepresent. Thus, “C₂-C₆ alkynyl” means an alkynyl radical having from 2 to6 carbon atoms. Alkynyl groups include ethynyl, propynyl, butynyl,3-methylbutynyl and so on. The straight, branched or cyclic portion ofthe alkynyl group can contain triple bonds and can be substituted if asubstituted alkynyl group is indicated.

“Cycloalkyl” as used herein is intended to include non-aromatic cyclichydrocarbon groups, having the specified number of carbon atoms, whichmay or may not be bridged or structurally constrained. Examples of suchcycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, adamantyl, cyclooctyl, cycloheptyl,tetrahydro-naphthalene, methylenecylohexyl, and the like. As usedherein, examples of “C₃-C₁₀ cycloalkyl” can include, but are not limitedto:

“Alkoxy” represents either a cyclic or non-cyclic alkyl group ofindicated number of carbon atoms attached through an oxygen bridge.“Alkoxy” therefore encompasses the definitions of alkyl and cycloalkylabove.

“Perfluoroalkyl” represents alkyl chains of up to 10 carbon atoms havingexhaustive substitution of their corresponding hydrogens with fluorineatoms.

As used herein, “aryl” is intended to mean any stable monocyclic orbicyclic carbon ring of up to 7 atoms in each ring, wherein at least onering is aromatic. Examples of such aryl elements include, but are notlimited to, phenyl, naphthyl, tetrahydro-naphthyl, indanyl, or biphenyl.In cases where the aryl substituent is bicyclic and one ring isnon-aromatic, it is understood that attachment is via the aromatic ring.

The term heteroaryl, as used herein, represents a stable monocyclic orbicyclic ring of up to 7 atoms in each ring, wherein at least one ringis aromatic and contains from 1 to 4 heteroatoms chosen from O, N and S.Heteroaryl groups within the scope of this definition include but arenot limited to: azabenzimidazole, acridinyl, carbazolyl, cinnolinylbenzimidazolyl, benzofuranyl, benzothiophenyl, benzoxazolyl,benzothiazolyl, benzodihydrofuranyl, 1,3-benzodioxolyl,2,3-dihydro-1,4-benzodioxinyl, indolyl, quinolyl, quinoxalinyl,isoquinolyl, furanyl, thienyl, imidazolyl, oxazolyl, thiazolyl,isoxazolyl, isothiazolyl, pyrazolyl, pyrrolyl, pyridyl, pyrimidyl,pyrazinyl, piridazinyl, tetrahydroquinolinyl, thiadiazolyl, oxadiazolyl,triazolyl, imidizopyridinyl, tetrazolyl, and indanyl. As with thedefinition of heterocycle below, “heteroaryl” is also understood toinclude the N-oxide derivative of any nitrogen-containing heteroaryl. Incases where the heteroaryl substituent is bicyclic and one ring isnon-aromatic or contains no heteroatoms, it is understood thatattachment is via the aromatic ring or via the heteroatom containingring, respectively.

Whenever the term “alkyl” or “aryl” or either of their prefix rootsappears in a name of a substituent (e.g., aryl C₀₋₈ alkyl), it shall beinterpreted as including those limitations given above for “alkyl” and“aryl.” Designated numbers of carbon atoms (e.g., C₀₋₈) shall referindependently to the number of carbon atoms in an alkyl or cyclic alkylmoiety or to the alkyl portion of a larger substituent in which alkylappears as its prefix root.

As appreciated by those of skill in the art, “halo” or “halogen” as usedherein is intended to include chloro, fluoro, bromo and iodo.

The term “heterocycle” or “heterocyclyl” as used herein is intended tomean a 5- to 14-membered aromatic or nonaromatic ring system containingfrom 1 to 4 heteroatoms selected from the group consisting of 0, N andS, and includes bicyclic groups. “Heterocyclyl” therefore includes theabove mentioned heteroaryls, as well as dihydro and tetrathydro analogsthereof. Further examples of “heterocyclyl” include, but are not limitedto the following: azabenzimidazole, benzoimidazolyl, benzofuranyl,benzofurazanyl, benzopyrazolyl, benzotriazolyl, benzothiophenyl,benzoxazolyl, carbazolyl, carbolinyl, cinnolinyl, furanyl, imidazolyl,indolinyl, indolyl, indolazinyl, indazolyl, isobenzofuranyl, isoindolyl,isoquinolyl, isothiazolyl, isoxazolyl, naphthpyridinyl, oxadiazolyl,oxazolyl, oxazoline, isoxazoline, oxetanyl, pyranyl, pyrazinyl,pyrazolyl, pyridazinyl, pyridopyridinyl, pyridazinyl, pyridinyl,pyrimidyl, pyrrolyl, quinazolinyl, quinolyl, quinoxalinyl,tetrahydropyranyl, tetrazolyl, tetrazolopyridyl, thiadiazolyl,thiazolyl, thienyl, triazolyl, azetidinyl, aziridinyl, 1,4-dioxanyl,hexahydroazepinyl, piperazinyl, piperidinyl, pyrrolidinyl, morpholinyl,thiomorpholinyl, dihydrobenzoimidazolyl, dihydrobenzofuranyl,dihydrobenzothiophenyl, dihydrobenzoxazolyl, dihydrofuranyl,dihydroimidazolyl, dihydroindolyl, dihydroisooxazolyl,dihydroisothiazolyl, dihydrooxadiazolyl, dihydrooxazolyl,dihydropyrazinyl, dihydropyrazolyl, dihydropyridinyl,dihydropyrimidinyl, dihydropyrrolyl, dihydroquinolinyl,dihydrotetrazolyl, dihydrothiadiazolyl, dihydrothiazolyl,dihydrothienyl, dihydrotriazolyl, dihydroazetidinyl,methylenedioxybenzoyl, tetrahydrofuranyl, and tetrahydrothienyl, andN-oxides thereof. Attachment of a heterocyclyl substituent can occur viaa carbon atom or via a heteroatom.

The terms “arylalkyl” and “alkylaryl” include an alkyl portion wherealkyl is as defined above and include an aryl portion where aryl is asdefined above. Examples of arylalkyl include, but are not limited to,benzyl, phenylethyl, phenylpropyl, naphthylmethyl, and naphthylethyl.Examples of alkylaryl include, but are not limited to, toluene,ethylbenzene, propylbenzene, methylpyridine, ethylpyridine,propylpyridine and butylpyridine.

In addition, the compounds disclosed herein can exist as tautomers andboth tautomeric forms are intended to be encompassed by the scope of theinvention, even though only one tautomeric structure is depicted. Forexample, any claim to compound A below is understood to includetautomeric structure B, and vice versa, as well as mixtures thereof. Theterm

represents the remainder of the 4-azasteroid derivatives of the presentinvention.

The term “oxy” means an oxygen (O) atom. The term “thio” means a sulfur(S) atom. The term “oxo” means “═O”. The term “carbonyl” means “C═O.”

The term “substituted” shall be deemed to include multiple degrees ofsubstitution by a named substituent. Where multiple substituent moietiesare disclosed or claimed, the substituted compound can be independentlysubstituted by one or more of the disclosed or claimed substituentmoieties, singly or plurally. By independently substituted, it is meantthat the (two or more) substituents can be the same or different.

When any variable (e.g., R¹, R², etc.) occurs more than one time in anysubstituent or in formula I, its definition in each occurrence isindependent of its definition at every other occurrence. Also,combinations of substituents and/or variables are permissible only ifsuch combinations result in stable compounds.

Under standard nomenclature used in this disclosure, the terminalportion of the designated side chain is described first, followed by theadjacent functionality toward the point of attachment. For example, aC₁₋₅ alkylcarbonylamino C₁₋₆ alkyl substituent is equivalent to

In choosing compounds of the present invention, one of ordinary skill inthe art will recognize that the various substituents, i.e. R¹, R², andR³, etc., are to be chosen in conformity with well-known principles ofchemical structure connectivity.

Lines drawn into the ring systems from substituents indicate that theindicated bond can be attached to any of the substitutable ring atoms.If the ring system is polycyclic, it is intended that the bond beattached to any of the suitable carbon atoms on the proximal ring only.

It is understood that substituents and substitution patterns on thecompounds of the instant invention can be selected by one of ordinaryskill in the art to provide compounds that are chemically stable andthat can be readily synthesized by techniques known in the art, as wellas those methods set forth below, from readily available startingmaterials. If a substituent is itself substituted with more than onegroup, it is understood that these multiple groups can be on the samecarbon or on different carbons, so long as a stable structure results.The phrase “optionally substituted with one or more substituents” shouldbe taken to be equivalent to the phrase “optionally substituted with atleast one substituent” and in such cases one embodiment will have fromzero to three substituents.

In one embodiment, a-b represents CH═CH. In another embodiment, a-b isCH₂CH₂.

In one embodiment of the invention, R², is chosen from hydrogen,hydroxyC₀₋₁₀alkyl, C₁₋₁₀alkyl, aryl C₀₋₁₀alkyl,C₃₋₈heterocyclylC₀₋₁₀alkyl, (C₀₋₁₀alkyl)₁₋₂aminocarbonyl-C₀₋₁₀ alkyl,C₃₋₈ heterocyclyl C₀₋₁₀ alkyl aminocarbonyl C₀₋₁₀ alkyl, C₀₋₁₀ alkylcarbonylamino C₁₋₁₀ alkyl, C₀₋₁₀ alkyloxy carbonyloxy C₀₋₁₀ alkyl, C₃₋₈cycloalkyl C₀₋₁₀ alkyloxy carbonyloxy-C₀₋₁₀ alkyl, C₃₋₈ heterocyclylC₀₋₁₀ alkyloxy-carbonyloxy C₀₋₁₀ alkyl, aryl C₀₋₁₀ alkyloxy carbonyloxyC₀₋₁₀ alkyl, C₁₋₁₀ alkoxy-(carbonyl)₀₋₁C₀₋₁₀ alkyl,C₁₋₁₀alkyloxy-C₀₋₁₀alkyl, aryloxy C₀₋₁₀ alkyl, C₃₋₈ cycloalkyloxy C₀₋₁₀alkyl, C₃₋₈ heterocyclyloxy C₀₋₁₀ alkyl, C₃₋₈ heterocyclylC₀₋₁₀ alkyloxyC₀₋₁₀ alkyl, and C₁₋₁₀ alkylcarbonyloxy C₀₋₁₀ alkyl.

In one variant of this embodiment, R², is chosen from hydrogen,hydroxyC₀₋₁₀alkyl, C₁₋₁₀ alkyl, aryl C₀₋₁₀ alkyl, C₃₋₈ heterocyclylC₀₋₁₀ alkyl, C₃₋₈ heterocyclyl C₀₋₁₀ alkyl-aminocarbonyl C₀₋₁₀ alkyl,C₀₋₁₀ alkyl carbonylamino C₁₋₁₀ alkyl, C₁₋₁₀ alkoxy(carbonyl)₀₋₁C₀₋₁₀alkyl, C₁₋₁₀alkyloxyC₀₋₁₀alkyl, aryloxy C₀₋₁₀ alkyl, C₃₋₈heterocyclyloxy C₀₋₁₀ alkyl, C₃₋₈ heterocyclylC₀₋₁₀alkyloxy C₀₋₁₀ alkyl,and C₁₋₁₀ alkylcarbonyloxy C₀₋₁₀ alkyl.

In another embodiment, R², is chosen from perfluoroC₁₋₆alkyl,perfluoroC₁₋₆alkoxy, C₃₋₈ cycloalkyl C₀₋₁₀ alkyl, (C₀₋₁₀alkyl)₁₋₂aminocarbonyloxy C₀₋₁₀ alkyl, (aryl C₀₋₁₀alkyl)₁₋₂aminocarbonyloxy C₀₋₁₀ alkyl, (C₃₋₈ cycloalkyl C₀₋₁₀alkyl)₁₋₂aminocarbonyloxy C₀₋₁₀ alkyl, (C₃₋₈heterocyclyl C₀₋₁₀alkyl)₁₋₂aminocarbonyloxy C₀₋₁₀ alkyl, (C₀₋₁₀alkyl)₁₋₂aminocarbonylaminoC₁₋₁₀ alkyl, (aryl C₀₋₁₀alkyl)₁₋₂-aminocarbonylamino C₁₋₁₀ alkyl, (C₃₋₈ cycloalkyl C₀₋₁₀alkyl)₁₋₂aminocarbonylamino C₁₋₁₀ alkyl, (C₃₋₈ heterocyclyl C₀₋₁₀alkyl)₁₋₂aminocarbonylamino C₁₋₁₀ alkyl, (aryl C₀₋₁₀alkyl)₁₋₂aminocarbonyl C₀₋₁₀ alkyl, C₃₋₈ cycloalkyl C₀₋₁₀ alkylaminocarbonyl C₀₋₁₀ alkyl, C₃₋₈ cycloalkyl C₀₋₁₀ alkyl carbonylaminoC₁₋₁₀ alkyl, C₃₋₈ heterocyclyl C₀₋₁₀ alkyl carbonylamino C₁₋₁₀ alkyl,aryl C₀₋₁₀ alkyl carbonylamino C₁₋₁₀ alkyl, C₀₋₁₀ alkyloxy-carbonylaminoC₁₋₁₀ alkyl, C₃₋₈ cycloalkyl C₀₋₁₀ alkyloxy carbonylamino C₁₋₁₀ alkyl,C₃₋₈ heterocyclyl C₀₋₁₀ alkyloxy carbonylamino C₁₋₁₀ alkyl, and arylC₀₋₁₀ alkyloxy carbonylamino C₁₋₁₀ alkyl.

In one embodiment of the invention, R³ is chosen from halogen, aryl,C₁₋₈ alkyl, arylC₁₋₆ alkyl, aminoC₀₋₆ alkyl, aryl-C₀₋₆ alkylaminoC₀₋₆alkyl, hydroxy-C₀₋₆ alkyl, C₁₋₆ alkylthio, aryl-C₀₋₆ alkylthio, C₁₋₆alkoxy-C₀₋₆ alkyl, aryl-C₀₋₆ alkoxy-C₀₋₆ alkyl, cyano, and nitro.

In another embodiment of the invention, invention R³ is chosen fromhalogen, C₃₋₈ cycloalkyl, C₃₋₈ cycloheteroalkyl, C₁₋₆ alkylaminoC₀₋₆alkyl, (C₁₋₆ alkyl)₂aminoC₀₋₆ alkyl, arylC₀₋₆ alkylaminoC₀₋₆ alkyl,(aryl-C₀₋₆ alkyl)₂aminoC₀₋₆ alkyl, C₁₋₆ alkylsulfinyl, aryl-C₀₋₆alkylsulfinyl, C₁₋₆ alkylsulfonyl, arylC₀₋₆ alkylsulfonyl,hydroxycarbonylC₀₋₆ alkyl, C₁₋₆ alkoxycarbonyl-C₀₋₆ alkyl, aryl-C₀₋₆alkoxycarbonyl-C₀₋₆ alkyl, hydroxycarbonylC₁₋₆ alkyloxy, perfluoro-C₁₋₄alkyl, perfluoro-C₁₋₄ alkoxy, C₁₋₆ alkylcarbonyloxy,arylC₀₋₆alkylcarbonyloxy, C₁₋₆alkylcarbonylamino, aryl-C₀₋₆alkylcarbonylamino, C₁₋₆ alkylsulfonylamino, aryl-C₀₋₆alkylsulfonylamino, C₁₋₆ alkoxycarbonylamino, aryl-C₀₋₆alkoxycarbonylamino, C₁₋₆ alkylaminocarbonylamino, aryl-C₀₋₆alkylaminocarbonylamino, (C₁₋₆ alkyl)₂ aminocarbonylamino, (aryl-C₀₋₆alkyl)₂ aminocarbonylamino, (C₁₋₆ alkyl)₂ aminocarbonyloxy, and(aryl-C₀₋₆ alkyl)₂ aminocarbonyloxy.

Compounds of the present invention have been found to be tissue-selective modulators of the androgen receptor (SARMs). In one aspect,compounds of the present invention can be useful to activate thefunction of the androgen receptor in a mammal, and in particular toactivate the function of the androgen receptor in bone and/or muscletissue and block or inhibit (“antagonize”) the function of the androgenreceptor in the prostate of a male individual or in the uterus of afemale individual.

A further aspect of the present invention is the use of compounds offormula I to attenuate or block the function of the androgen receptor inthe prostate of a male individual or in the uterus of a femaleindividual induced by AR agonists, but not in hair-growing skin or vocalcords, and activate the function of the androgen receptor in bone and/ormuscle tissue, but not in organs which control blood lipid levels (e.g.liver).

Representative compounds of the present invention typically displaysubmicromolar binding affinity for the androgen receptor. Compounds ofthis invention are therefore useful in treating mammals suffering fromdisorders related to androgen receptor function. Therapeuticallyeffective amounts of the compound, including the pharmaceuticallyacceptable salts thereof, are administered to the mammal, to treatdisorders related to androgen receptor function, such as, androgendeficiency, disorders which can be ameliorated by androgen replacement,or which can be improved by androgen replacement, including: enhancementof weakened muscle tone, osteoporosis, osteopenia,glucocorticoid-induced osteoporosis, periodontal disease, bone fracture(for example, vertebral and non-vertebral fractures), bone damagefollowing bone reconstructive surgery, sarcopenia, frailty, aging skin,male hypogonadism, postmenopausal symptoms in women, atherosclerosis,hypercholesterolemia, hyperlipidemia, obesity, aplastic anemia and otherhematopoietic disorders, pancreatic cancer, inflammatory arthritis andjoint repair, IIV-wasting, prostate cancer, benign prostatic hyperplasia(BPH), cancer cachexia, Alzheimer's disease, muscular dystrophies,cognitive decline, sexual dysfunction, sleep apnea, depression,premature ovarian failure, and autoimmune disease. Treatment is effectedby administration of a therapeutically effective amount of a compound ofstructural formula I to a mammal in need of such treatment. In addition,these compounds are useful as ingredients in pharmaceutical compositionsalone or in combination with other active agents.

In one embodiment, the compounds of the present invention can be used totreat conditions in a male individual which are caused by androgendeficiency or which can be ameliorated by androgen replacement,including, but not limited to, osteoporosis, osteopenia,glucocorticoid-induced osteoporosis, periodontal disease, HIV-wasting,prostate cancer, cancer cachexia, obesity, arthritic conditions,anemias, such as for example, aplastic anemia, muscular dystrophies, andAlzheimer's disease, cognitive decline, sexual dysfunction, sleep apnea,depression, benign prostatic hyperplasia (BPH), abdominal obesity,metabolic syndrome, type II diabetes, and atherosclerosis, alone or incombination with other active agents. Treatment is effected byadministration of a therapeutically effective amount of a compound ofstructural formula I to a male individual in need of such treatment.

“Arthritic condition” or “arthritic conditions” refers to a diseasewherein inflammatory lesions are confined to the joints or anyinflammatory conditions of the joints, most notably osteoarthritis andrheumatoid arthritis (Academic Press Dictionary of Science Technology;Academic Press; 1st edition, Jan. 15, 1992). The compounds of Formula Iare also useful, alone or in combination, to treat or prevent arthriticconditions, such as Behcet's disease; bursitis and tendinitis; CPPDdeposition disease; carpal tunnel syndrome; Ehlers-Danlos syndrome;fibromyalgia; gout; infectious arthritis; inflammatory bowel disease;juvenile arthritis; lupus erythematosus; lyme disease; marfan syndrome;myositis; osteoarthritis; osteogenesis imperfecta; osteonecrosis;polyarteritis; polymyalgia rheumatica; psoriatic arthritis; Raynaud'sphenomenon; reflex sympathetic dystrophy syndrome; Reiter's syndrome;rheumatoid arthritis; scleroderma; and Sjogren's syndrome. An embodimentof the invention encompasses the treatment or prevention of an arthriticcondition which comprises administering a therapeutically effectiveamount of a Compound of Formula I. A subembodiment is the treatment orprevention of osteoarthritis, which comprises administering atherapeutically effective amount of a Compound of Formula I. See: CutoloM, et al., Ann. N.Y. Acad. Sci. 2002June; 966:131-42; Cutolo, M. RheumDis Clin North Am 2000November;26(4):881-95; Bijlsma J W, et al., Am JReprod Immunol 1992October-December 28(3-4):231-4; Jansson L, et al.;Arthritis Rheum 2001September; 44(9):2168-75; and Purdie D W. Br MedBull 2000; 56(3):809-23. Also, see Merck Manual, 17th edition, pp.449-451.

When used in combination to treat arthritic conditions, the compounds ofFormula I can be used with any of the drugs disclosed herein as usefulfor combination therapy, or can be used with drugs known to treat orprevent arthritic conditions, such as corticosteroids, cytoxic drugs (orother disease modifying or remission inducing drugs), gold treatment,methotrexate, NSAIDs, and COX-2 inhibitors.

In another embodiment, the compounds of the present invention can beused to treat conditions in a female individual which are caused byandrogen deficiency or which can be ameliorated by androgen replacement,including, but not limited to, osteoporosis, osteopenia, aging skin,glucocorticoid-induced osteoporosis, postmenopausal symptoms,periodontal disease, HIV-wasting, cancer cachexia, obesity, anemias,such as for example, aplastic anemia, muscular dystrophies, Alzheimer'sdisease, premature ovarian failure, cognitive decline, sexualdysfunction, depression, inflammatory arthritis and joint repair,atherosclerosis, and autoimmune disease, alone or in combination withother active agents. Treatment is effected by administration of atherapeutically effective amount of a compound of structural formula Ito a female individual in need of such treatment.

The compounds of formula I are also useful in the enhancement of muscletone in mammals, such as for example, humans. The compounds ofstructural formula I can also be employed as adjuncts to traditionalandrogen depletion therapy in the treatment of prostate cancer torestore bone, minimize bone loss, and maintain bone mineral density. Inthis manner, they can be employed together with traditional androgendeprivation therapy, including GnRH agonists/antagonists, such as thosedisclosed in P. Limonta, et al., Exp. Opin. Invest. Drugs, 10: 709-720(2001); H. J. Stricker, Urology, 58 (Suppl. 2A): 24-27 (2001); R. P.Millar, et al., British Medical Bulletin, 56: 761-772 (2000); and A. V.Schally et al., Advanced Drug Delivery Reviews, 28: 157-169 (1997). Thecompounds of structural formula I can be used in combination withantiandrogens, such as flutamide, 2-hydroxyflutamide (the activemetabolite of flutamide), nilutamide, and bicalutamide (Casodex™) in thetreatment of prostate cancer.

Further, the compounds of the present invention can also be employed inthe treatment of pancreatic cancer, either for their androgen antagonistproperties or as an adjunct to an antiandrogen, such as flutamide,2-hydroxyflutamide (the active metabolite of flutamide), nilutamide, andbicalutamide (Casodex™).

The term “treating cancer” or “treatment of cancer” refers toadministration to a mammal afflicted with a cancerous condition andrefers to an effect that alleviates the cancerous condition by killingthe cancerous cells, but also to an effect that results in theinhibition of growth and/or metastasis of the cancer.

Compounds of structural formula I can minimize the negative effects onlipid metabolism. Therefore, considering their tissue selective androgenagonistic properties, the compounds of this invention exhibit advantagesover existing approaches for hormone replacement therapy in hypogonadic(androgen deficient) male individuals.

Additionally, compounds of the present invention can increase the numberof blood cells, such as red blood cells and platelets, and can be usedfor treatment of hematopoietic disorders, such as aplastic anemia.

In one embodiment of the invention, therapeutically effective amounts ofthe compound of Formula I, are administered to the mammal, to treat orimprove disorders selected from enhancement of weakened muscle tone,osteoporosis, osteopenia, glucocorticoid-induced osteoporosis,periodontal disease, bone fracture, bone damage following bonereconstructive surgery, sarcopenia, frailty, aging skin, malehypogonadism, postmenopausal symptoms in women, atherosclerosis,hypercholesterolemia, hyperlipidemia, obesity, aplastic anemia and otherhematopoietic disorders, pancreatic cancer, inflammatory arthritis andjoint repair, HIV-wasting, prostate cancer, benign prostatic hyperplasia(BPH), cancer cachexia, Alzheimer's disease, muscular dystrophies,cognitive decline, sexual dysfunction, sleep apnea, depression,premature ovarian failure, and autoimmune disease.

In another embodiment, therapeutically effective amounts of the compoundcan be used to treat or improve a disorder selected from weakened muscletone, osteoporosis, osteopenia, glucocorticoid-induced osteoporosis,periodontal disease, bone fracture, bone damage following bonereconstructive surgery, sarcopenia, Alzheimer's disease, and frailty.

In another embodiment, the compound in accordance with the invention canbe used to treat or improve a disorder such as male hypogonadism,postmenopausal symptoms in women, atherosclerosis, hypercholesterolemia,hyperlipidemia, obesity, aplastic anemia and other hematopoieticdisorders, pancreatic cancer, inflammatory arthritis and joint repair,HIV-wasting, prostate cancer, benign prostatic hyperplasia (BPH), cancercachexia, muscular dystrophies, cognitive decline, sexual dysfunction,sleep apnea, depression, premature ovarian failure, and autoimmunedisease.

The compounds of the present invention can be administered in theirenantiomerically pure form. Racemic mixtures can be separated into theirindividual enantiomers by any of a number of conventional methods. Theseinclude chiral chromatography, derivatization with a chiral auxiliaryfollowed by separation by chromatography or crystallization, andfractional crystallization of diastereomeric salts.

As used herein, a compound of the present invention which functions asan “agonist” of the androgen receptor can bind to the androgen receptorand initiate a physiological or a pharmacological responsecharacteristic of that receptor. The term “tissue-selective androgenreceptor modulator” refers to an androgen receptor ligand that mimicsthe action of a natural ligand in some tissues but not in others. A“partial agonist” is an agonist which is unable to induce maximalactivation of the receptor population, regardless of the amount ofcompound applied. A “full agonist” induces full activation of theandrogen receptor population at a given concentration. A compound of thepresent invention which functions as an “antagonist” of the androgenreceptor can bind to the androgen receptor and block or inhibit theandrogen-associated responses normally induced by a natural androgenreceptor ligand.

The term “pharmaceutically acceptable salts” refers to salts preparedfrom pharmaceutically acceptable non-toxic bases or acids includinginorganic or organic bases and inorganic or organic acids. Non-limitingrepresentative salts derived from inorganic bases include aluminum,ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganicsalts, manganous, potassium, sodium, zinc, and the like. In one variantof the invention, the salts are chosen from the ammonium, calcium,lithium, magnesium, potassium, and sodium salts. Non-limiting examplesof salts derived from pharmaceutically acceptable organic non-toxicbases include salts of primary, secondary, and tertiary amines,substituted amines including naturally occurring substituted amines,cyclic amines, and basic ion exchange resins, such as arginine, betaine,caffeine, choline, N,N′-dibenzylethylenediamine, diethylamine,2-diethylaninoethanol, 2-dimethylaminoethanol, ethanolamine,ethylenediamine, N-ethyl-morpholine, N-ethylpiperidine, glucamine,glucosamine, histidine, hydrabamine, isopropylamine, lysine,methylglucamine, morpholine, piperazine, piperidine, polyamine resins,procaine, purines, theobromine, triethylamine, trimethylamine,tripropylamine, tromethamine, and the like.

When the compound of the present invention is basic, salts can beprepared from pharmaceutically acceptable non-toxic acids, includinginorganic and organic acids. Representative acids which can be employedinclude acetic, benzenesulfonic, benzoic, camphorsulfonic, citric,ethanesulfonic, formic, fumaric, gluconic, glutamic, hydrobromic,hydrochloric, isethionic, lactic, maleic, malic, mandelic,methanesulfonic, malonic, mucic, nitric, pamoic, pantothenic,phosphoric, propionic, succinic, sulfuric, tartaric, p-toluenesulfonicacid, trifluoroacetic acid, and the like. In one variant, the acids areselected from citric, fumaric, hydrobromic, hydrochloric, maleic,phosphoric, sulfuric, and tartaric acids.

The preparation of the pharmaceutically acceptable salts described aboveand other typical pharmaceutically acceptable salts is more fullydescribed by Berg et al., “Pharmaceutical Salts,” J. Pharm. Sci.,1977:66:1-19.

It would also be noted that the compounds of the present invention arepotentially internal salts or zwitterions, since under physiologicalconditions a deprotonated acidic moiety in the compound, such as acarboxyl group, may be anionic, and this electronic charge might then bebalanced off internally against the cationic charge of a protonated oralkylated basic moiety, such as a quaternary nitrogen atom.

The term “therapeutically effective amount” means the amount thecompound of structural formula I that will elicit the biological ormedical response of a tissue, system, animal or human that is beingsought by the researcher, veterinarian, medical doctor or otherclinician.

The term “composition” as used herein is intended to encompass a productcomprising the specified ingredients in the specified amounts, as wellas any product which results, directly or indirectly, from combinationof the specified ingredients in the specified amounts.

By “pharmaceutically acceptable” it is meant that the carrier, diluentor excipient must be compatible with the other ingredients of theformulation and not be deleterious to the recipient thereof.

The terms “administration of a compound” and “administering a compound”should be understood to mean providing a compound of the invention or aprodrug of a compound of the invention to the individual in need oftreatment.

By the term “modulating a function mediated by the androgen receptor ina tissue selective manner” it is meant modulating a function mediated bythe androgen receptor selectively (or discriminately) in anabolic (boneand/or muscular) tissue (bone and muscular) in the absence of suchmodulation at androgenic (reproductive) tissue, such as the prostate,testis, seminal vesicles, ovary, uterus, and other sex accessorytissues. In one embodiment, the function of the androgen receptor inanabolic tissue is activated whereas the function of the androgenreceptor in androgenic tissue is blocked or suppressed. In anotherembodiment, the function of the androgen receptor in anabolic tissue isblocked or suppressed whereas the function of the androgen receptor inandrogenic tissue is activated.

The administration of a compound of structural formula I in order topractice the present methods of therapy is carried out by administeringan effective amount of the compound of structural formula I to thepatient in need of such treatment or prophylaxis. The need for aprophylactic administration according to the methods of the presentinvention is determined via the use of well-known risk factors. Theeffective amount of an individual compound is determined, in the finalanalysis, by the physician in charge of the case, but depends on factorssuch as the exact disease to be treated, the severity of the disease andother diseases or conditions from which the patient suffers, the chosenroute of administration, other drugs and treatments which the patientcan concomitantly require, and other factors in the physician'sjudgment.

If formulated as a fixed dose, such combination products employ thecompounds of this invention within the dosage range described below andthe other pharmaceutically active agent(s) within its approved dosagerange. Compounds of the instant invention can alternatively be usedsequentially with known pharmaceutically acceptable agent(s) when acombination formulation is inappropriate.

Generally, the daily dosage of a compound of structural formula I can bevaried over a wide range from about 0.01 to about 1000 mg per adulthuman per day. For example, dosages range from about 0.1 to about 200mg/day. For oral administration, the compositions can be provided in theform of tablets containing from about 0.01 to about 1000 mg, such as forexample, 0.01, 0.05, 0.1, 0.5, 1.0, 2.5, 3.0, 5.0, 6.0, 10.0, 15.0,25.0, 50.0, 75, 100, 125, 150, 175, 180, 200, 225, and 500 milligrams ofthe active ingredient for the symptomatic adjustment of the dosage tothe mammal to be treated.

The dose can be administered in a single daily dose or the total dailydosage can be administered in divided doses of two, three or four timesdaily. Furthermore, based on the properties of the individual compoundselected for administration, the dose can be administered lessfrequently, e.g., weekly, twice weekly, monthly, etc. The unit dosagewill, of course, be correspondingly larger for the less frequentadministration.

When administered via intranasal routes, transdermal routes, by rectalor vaginal suppositories, or through an intravenous solution, the dosageadministration will, of course, be continuous rather than intermittentthroughout the dosage regimen.

Exemplifying the invention is a pharmaceutical composition comprisingany of the compounds described above and a pharmaceutically acceptablecarrier. Also exemplifying the invention is a pharmaceutical compositionmade by combining any of the compounds described above and apharmaceutically acceptable carrier. An illustration of the invention isa process for making a pharmaceutical composition comprising combiningany of the compounds described above and a pharmaceutically acceptablecarrier.

Formulations of the tissue-selective androgen receptor modulatoremployed in the present method for medical use comprise a compound ofstructural formula I together with an acceptable carrier thereof andoptionally other therapeutically active ingredients. The carrier must bepharmaceutically acceptable in the sense of being compatible with theother ingredients of the formulation and not being deleterious to therecipient subject of the formulation.

The present invention, therefore, further provides a pharmaceuticalformulation comprising a compound of structural formula I together witha pharmaceutically acceptable carrier thereof. The formulations includethose suitable for oral, rectal, intravaginal, intranasal, topical andparenteral (including subcutaneous, intramuscular and intravenousadministration). In one embodiment, the formulations are those suitablefor oral administration.

Suitable topical formulations of a compound of formula I includetransdermal devices, aerosols, creams, solutions, ointments, gels,lotions, dusting powders, and the like. The topical pharmaceuticalcompositions containing the compounds of the present inventionordinarily include about 0.005% to about 5% by weight of the activecompound in admixture with a pharmaceutically acceptable vehicle.Transdermal skin patches useful for administering the compounds of thepresent invention include those well known to those of ordinary skill inthat art.

The formulations can be presented in a unit dosage form and can beprepared by any of the methods known in the art of pharmacy. All methodsinclude the step of bringing the active compound in association with acarrier, which constitutes one or more ingredients. In general, theformulations are prepared by uniformly and intimately bringing theactive compound in association with a liquid carrier, a waxy solidcarrier or a finely divided solid carrier, and then, if needed, shapingthe product into the desired dosage form.

Formulations of the present invention suitable for oral administrationcan be presented as discrete units such as capsules, cachets, tablets orlozenges, each containing a predetermined amount of the active compound;as a powder or granules; or a suspension or solution in an aqueousliquid or non-aqueous liquid, e.g., a syrup, an elixir, or an emulsion.

A tablet can be made by compression or molding, optionally with one ormore accessory ingredients. Compressed tablets can be prepared bycompressing in a suitable machine the active compound in a free flowingform, e.g., a powder or granules, optionally mixed with accessoryingredients, e.g., binders, lubricants, inert diluents, disintegratingagents or coloring agents. Molded tablets can be made by molding in asuitable machine a mixture of the active compound, preferably inpowdered form, with a suitable carrier. Suitable binders include,without limitation, starch, gelatin, natural sugars such as glucose orbeta-lactose, corn sweeteners, natural and synthetic gums such asacacia, tragacanth or sodium alginate, carboxymethyl-cellulose,polyethylene glycol, waxes and the like. Non-limiting representativelubricants used in these dosage forms include sodium oleate, sodiumstearate, magnesium stearate, sodium benzoate, sodium acetate, sodiumchloride and the like. Disintegrators include, without limitation,starch, methyl cellulose, agar, bentonite, xanthan gum and the like.

Oral liquid forms, such as syrups or suspensions in suitably flavoredsuspending or dispersing agents such as the synthetic and natural gums,for example, tragacanth, acacia, methyl cellulose and the like, can bemade by adding the active compound to the solution or suspension.Additional dispersing agents which can be employed include glycerin andthe like.

Formulations for vaginal or rectal administration can be presented as asuppository with a conventional carrier, i.e., a base that is nontoxicand nonirritating to mucous membranes, compatible with a compound ofstructural formula I, and is stable in storage and does not bind orinterfere with the release of the compound of structural formula I.Suitable bases include: cocoa butter (theobroma oil), polyethyleneglycols (such as carbowax and polyglycols), glycol-surfactantcombinations, polyoxyl 40 stearate, polyoxyethylene sorbitan fatty acidesters (such as Tween, Myrj, and Arlacel), glycerinated gelatin, andhydrogenated vegetable oils. When glycerinated gelatin suppositories areused, a preservative such as methylparaben or propylparaben can beemployed.

Topical preparations containing the active drug component can be admixedwith a variety of carrier materials well known in the art, such as,e.g., alcohols, aloe vera gel, allantoin, glycerine, vitamin A and Eoils, mineral oil, PPG2 myristyl propionate, and the like, to form,e.g., alcoholic solutions, topical cleansers, cleansing creams, skingels, skin lotions, and shampoos in cream or gel formulations.

The compounds of the present invention can also be administered in theform of liposome delivery systems, such as small unilamellar vesicles,large unilamellar vesicles and multilamellar vesicles. Liposomes can beformed from a variety of phospholipids, such as cholesterol,stearylamine or phosphatidylcholines.

Compounds of the present invention can also be delivered by the use ofmonoclonal antibodies as individual carriers to which the compoundmolecules are coupled. The compounds of the present invention can alsobe coupled with soluble polymers as targetable drug carriers. Suchpolymers can include polyvinyl-pyrrolidone, pyran copolymer,polyhydroxypropylmethacrylamide-phenol,polyhydroxy-ethylaspartamidephenol, or polyethylene-oxide polylysinesubstituted with palmitoyl residues. Furthermore, the compounds of thepresent invention can be coupled to a class of biodegradable polymersuseful in achieving controlled release of a drug, for example,polylactic acid, polyepsilon caprolactone, polyhydroxy butyric acid,polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates andcross-linked or amphipathic block copolymers of hydrogels.

Formulations suitable for parenteral administration include formulationsthat comprise a sterile aqueous preparation of the active compound whichcan be isotonic with the blood of the recipient. Such formulationssuitably comprise a solution or suspension of a compound that isisotonic with the blood of the recipient subject. Such formulations cancontain distilled water, 5% dextrose in distilled water or saline andthe active compound. Often it is useful to employ a pharmaceutically andpharmacologically acceptable acid addition salt of the active compoundthat has appropriate solubility for the solvents employed. Usefulformulations also comprise concentrated solutions or solids comprisingthe active compound which on dilution with an appropriate solvent give asolution suitable for parenteral administration.

The pharmaceutical composition and method of the present invention canfurther comprise other therapeutically active compounds usually appliedin the treatment of the above mentioned conditions, includingosteoporosis, periodontal disease, bone fracture, bone damage followingbone reconstructive surgery, sarcopenia, frailty, aging skin, malehypogonadism, post-menopausal symptoms in women, atherosclerosis,hypercholesterolemia, hyperlipidemia, hematopoietic disorders, such asfor example, aplastic anemia, pancreatic cancer, Alzheimer's disease,inflammatory arthritis, and joint repair.

For the treatment and prevention of osteoporosis, the compounds of thepresent invention can be administered in combination with at least onebone-strengthening agent selected from antiresorptive agents,osteoanabolic agents, and other agents beneficial for the skeletonthrough mechanisms which are not precisely defined, such as calciumsupplements, flavonoids, and vitamin D analogs. The conditions ofperiodontal disease, bone fracture, and bone damage following bonereconstructive surgery can also benefit from these combined treatments.For example, the compounds of the instant invention can be effectivelyadministered in combination with effective amounts of other agents suchas estrogens, bisphosphonates, SERMs, cathepsin K inhibitors, αvβ3integrin receptor antagonists, vacuolar ATPase inhibitors, thepolypeptide osteoprotegerin, antagonists of VEGF, thiazolidinediones,calcitonin, protein kinase inhibitors, parathyroid hormone (PTH) andanalogs, calcium receptor antagonists, growth hormone secretagogues,growth hormone releasing hormone, insulin-like growth factor, bonemorphogenetic protein (BMP), inhibitors of BMP antagonism, prostaglandinderivatives, fibroblast growth factors, vitamin D and derivativesthereof, vitamin K and derivatives thereof, soy isoflavones, calciumsalts, and fluoride salts. The conditions of periodontal disease, bonefracture, and bone damage following bone reconstructive surgery can alsobenefit from these combined treatments.

In one embodiment of the present invention, a compound of the instantinvention can be effectively administered in combination with aneffective amount of at least one bone-strengthening agent chosen fromestrogen, and estrogen derivatives, alone or in combination withprogestin or progestin derivatives; bisphosphonates; antiestrogens orselective estrogen receptor modulators; αvβ3 integrin receptorantagonists; cathepsin K inhibitors; osteoclast vacuolar ATPaseinhibitors; calcitonin; and osteoprotegerin.

In the treatment of osteoporosis, the activity of the compounds of thepresent invention are distinct from that of the anti-resorptive agents:estrogens, bisphosphonates, SERMs, calcitonin, cathepsin K inhibitors,vacuolar ATPase inhibitors, agents interfering with theRANK/RANKL/Osteoprotegerin pathway, p38 inhibitors or any otherinhibitors of osteoclast generation or osteoclast activation. Ratherthan inhibiting bone resorption, the compounds of structural formula Iaid in the stimulation of bone formation, acting, for example, oncortical bone, which is responsible for a significant part of bonestrength. The thickening of cortical bone substantially contributes to areduction in fracture risk, especially fractures of the hip. Thecombination of the tissue-SARMs of structural formula I withanti-resorptive agents such as for example estrogen or estrogenderivatives, bisphosphonates, antiestrogens, SERMs, calcitonin, αvβ3integrin receptor antagonists, HMG-CoA reductase inhibitors, vacuolarATPase inhibitors, and cathepsin K inhibitors is particularly useful dueto the complementary effect of the bone anabolic and antiresorptiveactions.

Non-limiting representatives of estrogen and estrogen derivativesinclude steroidal compounds having estrogenic activity such as, forexample, 17β-estradiol, estrone, conjugated estrogen (PREMAIN®), equineestrogen, 17β-ethynyl estradiol, and the like. The estrogen or estrogenderivative can be employed alone or in combination with a progestin orprogestin derivative. Nonlimiting examples of progestin derivatives arenorethindrone and medroxy-progesterone acetate.

Non-limiting examples of bisphosphonate compounds which can also beemployed in combination with a compound of the present inventioninclude:

-   (a) alendronate (also known as alendronic acid,    4-amino-1-hydroxybutylidene-1,1-bisphosphonic acid, alendronate    sodium, alendronate monosodium trihydrate or    4-amino-1-hydroxybutylidene-1,1-bisphosphonic acid monosodium    trihydrate. Alendronate is described in U.S. Pat. No. 4,922,007, to    Kieczykowski et al., issued May 1, 1990; U.S. Pat. No. 5,019,651, to    Kieczykowski, issued May 28, 1991; U.S. Pat. No. 5,510,517, to Dauer    et al., issued Apr. 23, 1996; U.S. Pat. No. 5,648,491, to Dauer et    al., issued Jul. 15, 1997;-   (b) [(cycloheptylamino)-methylene]-bis-phosphonate (incadronate),    which is described in U.S. Pat. No. 4,970,335, to Isomura et al.,    issued Nov. 13, 1990;-   (c) (dichloromethylene)-bis-phosphonic acid (clodronic acid) and the    disodium salt (clodronate), which are described in Belgium Patent    672,205 (1966) and J. Org. Chem 32, 4111 (1967);-   (d) [1-hydroxy-3-(1-pyrrolidinyl)-propylidene]-bis-phosphonate    (EB-1053);-   (e) (1-hydroxyethylidene)-bis-phosphonate (etidronate);-   (f) [1-hydroxy-3-(methylpentylamino)propylidene]-bis-phosphonate    (ibandronate), which is described in U.S. Pat. No. 4,927,814, issued    May 22, 1990;-   (g) (6-amino-1-hydroxyhexylidene)-bis-phosphonate (neridronate);-   (h) [3-(dimethylamino)-1-hydroxypropylidene]-bis-phosphonate    (olpadronate);-   (i) (3-amino-1-hydroxypropylidene)-bis-phosphonate (pamidronate);-   (j) [2-(2-pyridinyl)ethylidene]-bis-phosphonate (piridronate), which    is described in U.S. Pat. No. 4,761,406;-   (k) [1-hydroxy-2-(3-pyridinyl)-ethylidene]-bis-phosphonate    (risedronate);-   (l) {[(4-chlorophenyl)thio]methylene}-bis-phosphonate (tiludronate),    which is described in U.S. Pat. No. 4,876,248, to Breliere et al.,    Oct. 24, 1989;-   (m) [1-hydroxy-2-(1H-imidazol-1-yl)ethylidene]-bis-phosphonate    (zoledronate); and-   (n)    [1-hydroxy-2-imidazopyridin-(1,2-a)-3-ylethylidene]-bis-phosphonate    (minodronate).

In one embodiment of the methods and compositions of the presentinvention, the bisphosphonate is chosen from alendronate, clodronate,etidronate, ibandronate, incadronate, minodronate, neridronate,olpadronate, pamidronate, piridronate, risedronate, tiludronate,zoledronate, pharmaceutically acceptable salts of these bisphosphonates,and mixtures thereof. In one variant, the bisphosphonate is selectedfrom alendronate, risedronate, zoledronate, ibandronate, tiludronate,and clodronate. In a subclass of this class, the bisphosphonate isalendronate, pharmaceutically acceptable salts and hydrates thereof, andmixtures thereof. A particular pharmaceutically acceptable salt ofalendronate is alendronate monosodium. Pharmaceutically acceptablehydrates of alendronate monosodium include the monohydrate and thetrihydrate. A particular pharmaceutically acceptable salt of risedronateis risedronate monosodium. Pharmaceutically acceptable hydrates ofrisedronate monosodium include the hemi-pentahydrate.

Still further, antiestrogenic compounds such as raloxifene (see, e.g.,U.S. Pat. No. 5,393,763), clomiphene, zuclomiphene, enclomiphene,nafoxidene, CI-680, CI-628, CN-55,945-27, Mer-25, U-11,555A, U-100A, andsalts thereof, and the like (see, e.g., U.S. Pat. Nos. 4,729,999 and4,894,373) can be employed in combination with a compound of structuralformula I in the methods and compositions of the present invention.These agents are also known as SERMs, or selective estrogen receptormodulators, agents known in the art to prevent bone loss by inhibitingbone resorption via pathways believed to be similar to those ofestrogens.

Non-limiting representatives of SERMs include, for example, tamoxifen,raloxifene, lasofoxifene, toremifene, azorxifene, EM-800, EM-652, TSE424, clomiphene, droloxifene, idoxifene, and levormeloxifene [Goldstein,et al., Human Reproduction Update, 6: 212-224 (2000); Lufkin, et al.,Rheumatic Disease Clinics of North America, 27: 163-185 (2001), and Ann.Rep. Med. Chem. 36: 149-158 (2001)].

αvβ3 Integrin receptor antagonists suppress bone resorption and can beemployed in combination with the SARMs of structural formula I for thetreatment of bone disorders including osteoporosis. Peptidyl as well aspeptidomimetic antagonists of the αvβ3 integrin receptor have beendescribed both in the scientific and patent literature. For example,reference is made to W. J. Hoekstra and B. L. Poulter, Curr. Med. Chem.5: 195-204 (1998) and references cited therein. Other αvβ3 antagonistsare described in R. M. Keenan et al., J. Med. Chem. 40: 2289-2292(1997); R. M. Keenan et al., Bioorg. Med. Chem. Lett. 8: 3165-3170(1998); and R. M. Keenan et al., Bioorg. Med. Chem. Lett. 8: 3171-3176(1998).

Other non-limiting representative examples of published patent andpatent applications that describe various αvβ3 integrin receptorantagonists include: U.S. Pat. Nos. 6,472,403; 6,017,926; 6,472,403;6,410,526; 6,048,861; and 6,090,944.

Cathepsin K, formerly known as cathepsin O2, is a cysteine protease andis described in PCT International Application Publication No. WO96/13523; U.S. Pat. Nos. 5,501,969 and 5,736,357. Cysteine proteases,specifically cathepsins, are linked to a number of disease conditions,such as tumor metastasis, inflammation, arthritis, and bone remodeling.At acidic pH's, cathepsins can degrade type-I collagen. Cathepsinprotease inhibitors can inhibit osteoclastic bone resorption byinhibiting the degradation of collagen fibers and are thus useful in thetreatment of bone resorption diseases, such as osteoporosis.Non-limiting examples of cathespin K inhibitors can be found in PCTInternational Publications WO 01/49288 and WO 01/77073.

Members of the class of IMG-CoA reductase inhibitors, known as the“statins,” have been found to trigger the growth of new bone, replacingbone mass lost as a result of osteoporosis (see The Wall Street Journal,Friday, Dec. 3, 1999, page B1). Therefore, the statins hold promise forthe treatment of bone resorption. Examples of HMG-CoA reductaseinhibitors include statins in their lactonized or dihydroxy open acidforms and pharmaceutically acceptable salts and esters thereof,including but not limited to lovastatin (see U.S. Pat. No. 4,342,767);simvastatin (see U.S. Pat. No. 4,444,784); dihydroxy open-acidsimvastatin, particularly the ammonium or calcium salts thereof;pravastatin, particularly the sodium salt thereof (see U.S. Pat. No.4,346,227); fluvastatin, particularly the sodium salt thereof (see U.S.Pat. No. 5,354,772); atorvastatin, particularly the calcium salt thereof(see U.S. Pat. No. 5,273,995); cerivastatin, particularly the sodiumsalt thereof (see U.S. Pat. No. 5,177,080), rosuvastatin, also known asZD-4522 (see U.S. Pat. No. 5,260,440) and pitavastatin, also referred toas NK-104, itavastatin, or nisvastatin (see PCT internationalapplication publication number WO 97/23200).

Osteoclast vacuolar ATPase inhibitors, also called proton pumpinhibitors, can be employed together with the SARMs of structuralformula I. The proton ATPase which is found on the apical membrane ofthe osteoclast has been reported to play a significant role in the boneresorption process. Therefore, this proton pump represents an attractivetarget for the design of inhibitors of bone resorption which arepotentially useful for the treatment and prevention of osteoporosis andrelated metabolic diseases [see C. Farina et al., DDT, 4: 163-172(1999)].

The angiogenic factor VEGF has been shown to stimulate thebone-resorbing activity of isolated mature rabbit osteoclasts viabinding to its receptors on osteoclasts [see M. Nakagawa et al., FEBSLetters, 473: 161-164 (2000)]. Therefore, the development of antagonistsof VEGF binding to osteoclast receptors, such as KDR/Flk-1 and Flt-1,can provide yet a further approach to the treatment or prevention ofbone resorption.

Activators of the peroxisome proliferator-activated receptor-□(PPAR□),such as the thiazolidinediones (TZD's), inhibit osteoclast-like cellformation and bone resorption in vitro. Results reported by R. Okazakiet al. in Endocrinology, 140: 5060-5065 (1999) point to a localmechanism on bone marrow cells as well as a systemic one on glucosemetabolism. Nonlimiting examples of PPAR□, activators include theglitazones, such as troglitazone, pioglitazone, rosiglitazone, and BRL49653.

Calcitonin can also be employed together with the SARMs of structuralformula I. Calcitonin is preferentially employed as salmon nasal spray(Azra et al., Calcitonin. 1996. In: J. P. Bilezikian, et al., Ed.,Principles of Bone Biology, San Diego: Academic Press; and Silverman,“Calcitonin,” Rheumatic Disease Clinics of North America, 27: 187-196,2001)

Protein kinase inhibitors can also be employed together with the SARMsof structural formula I. Kinase inhibitors include those disclosed in WO01/17562 and are in one embodiment selected from inhibitors of p38.Non-limiting examples of p38 inhibitors useful in the present inventioninclude SB 203580 [Badger et al., J. Pharmacol. Exp. Ther., 279:1453-1461 (1996)].

Osteoanabolic agents are those agents that are known to build bone byincreasing the production of the bone protein matrix. Such osteoanabolicagents include, for example, parathyroid hormone (PTH) and fragmentsthereof, such as naturally occurring PTH (1-84), PTH (1-34), analogsthereof, native or with substitutions and particularly parathyroidhormone subcutaneous injection. PTH has been found to increase theactivity of osteoblasts, the cells that form bone, thereby promoting thesynthesis of new bone (Modern Drug Discovery, Vol. 3, No. 8, 2000). Aninjectable recombinant form of human PTH, Forteo (teriparatide), hasreceived regulatory approval in the U.S. for the treatment ofosteoporosis.

Also useful in combination with the SARMs of the present invention arecalcium receptor antagonists which induce the secretion of PTH asdescribed by Gowen et al., J. Clin. Invest. 105: 1595-604 (2000).

Additional osteoanabolic agents include growth hormone secretagogues,growth hormone, growth hormone releasing hormone and the like can beemployed with the compounds according to structural formula I for thetreatment of osteoporosis. Representative growth hormone secretagoguesare disclosed in U.S. Pat. Nos. 3,239,345, 4,036,979, 4,411,890,5,206,235, 5,283,241, 5,284,841, 5,310,737, 5,317,017, 5,374,721,5,430,144, 5,434,261, 5,438,136, 5,494,919, 5,494,920, 5,492,916 and5,536,716; and articles, Science, 260, 1640-1643 (Jun. 11, 1993); Ann.Rep. Med. Chem., 28: 177-186 (1993); Bioorg. Med. Chem. Lett., 4:2709-2714 (1994); and Proc. Natl. Acad. Sci. USA, 92: 7001-7005 (1995).

Insulin-like growth factor (IGF) can also be employed together with theSARMs of structural formula I. Insulin-like growth factors can beselected from Insulin-like Growth Factor I, alone or in combination withIGF binding protein 3 and IGF II [See Johannson and Rosen, 1996, In:Bilezikian, et al., Ed., Principles of Bone Biology, San Diego: AcademicPress; and Ghiron et al., J. Bone Miner. Res. 10: 1844-1852 (1995)].

Bone morphogenetic protein (BMP) can also be employed together with theSARMs of structural formula I. Bone morphogenetic protein includes BMP2, 3, 5, 6, 7, as well as related molecules TGF beta and GDF 5 [Rosen etal., “Bone morphogenetic proteins,” 1996. In: J. P. Bilezikian, et al.,Ed., Principles of Bone Biology, San Diego: Academic Press; and Wang EA, Trends Biotechnol., 11: 379-383 (1993)].

Inhibitors of BMP antagonism can also be employed together with theSARMs of structural formula I. In one embodiment, BMP antagonistinhibitors are chosen from inhibitors of the BMP antagonists SOST,noggin, chordin, gremlin, and dan [see Massague and Chen, Genes Dev.,14: 627-644, 2000; Aspenberg et al., J. Bone Miner. Res. 16: 497-500,2001; and Brunkow et al., Am. J. Hum. Genet. 68: 577-89 (2001)].

The tissue-selective androgen receptor modulators of the presentinvention can also be combined with the polypeptide osteoprotegerin forthe treatment of conditions associated with bone loss, such asosteoporosis. The osteoprotegerin can be selected from mammalianosteoprotegerin and human osteoprotegerin. The polypeptideosteoprotegerin, a member of the tumor necrosis factor receptorsuper-family, is useful to treat bone diseases characterized byincreased bone loss, such as osteoporosis. Reference is made to U.S.Pat. No. 6,288,032.

Prostaglandin derivatives can also be employed together with the SARMsof structural formula I. Non-limiting representatives of prostaglandinderivatives are selected from agonists of prostaglandin receptors EP1,EP2, EP4, FP, IP and derivatives thereof [Pilbeam et al.,“Prostaglandins and bone metabolism,” 1996. In: Bilezikian, et al. Ed.Principles of Bone Biology, San Diego: Academic Press; Weinreb et al.,Bone, 28: 275-281 (2001)].

Fibroblast growth factors can also be employed together with the SARMsof structural formula I. Fibroblast growth factors include aFGF, bFGFand related peptides with FGF activity [Hurley Florkiewicz, “Fibroblastgrowth factor and vascular endothelial growth factor families,” 1996.In: J. P. Bilezikian, et al., Ed. Principles of Bone Biology, San Diego:Academic Press].

In addition to bone resorption inhibitors and osteoanabolic agents,there are also other agents known to be beneficial for the skeletonthrough mechanisms which are not precisely defined. These agents canalso be favorably combined with the SARMs of structural formula I.

Vitamin D, vitamin D derivatives and analogs can also be employedtogether with the SARMs of structural formula I. Vitamin D and vitamin Dderivatives include, for example, D₃ (cholecaciferol), D₂(ergocalciferol), 25-OH-vitamin D₃, 1α,25(OH)₂ vitamin D₃, 1α-OH-vitaminD₃, 1α-OH-vitamin D₂, dihydrotachysterol, 26,27-F6-1α,25(OH)₂ vitaminD₃, 19-nor-1α,25(OH)₂ vitamin D₃, 22-oxacalcitriol, calcipotriol,1α,25(OH)₂-16-ene-23-yne-vitamin D₃ (Ro 23-7553), EB 1089,20-epi-1α,25(OH)₂ vitamin D₃, KH1060, ED71, 1α,24(S)-(OH)₂ vitamin D₃,1α,24(R)-(OH)₂ vitamin D₃ [See, Jones G., “Pharmacological mechanisms oftherapeutics: vitamin D and analogs,” 1996. In: J. P. Bilezikian, et al.Ed. Principles of Bone Biology, San Diego: Academic Press].

Vitamin K and Vitamin K derivatives can also be employed together withthe SARMs of structural formula I. Vitamin K and vitamin K derivativesinclude menatetrenone (vitamin K2) [see Shiraki et al., J. Bone Miner.Res., 15: 515-521 (2000)].

Soy isoflavones, including ipriflavone, can be employed together withthe SARMs of structural formula I.

Fluoride salts, including sodium fluoride (NaF) and monosodiumfluorophosphate (MEP), can also be employed together with the SARMs ofstructural formula I. Dietary calcium supplements can also be employedtogether with the SARMs of structural formula I. Dietary calciumsupplements include calcium carbonate, calcium citrate, and naturalcalcium salts (Heaney. Calcium. 1996. In: J. P. Bilezikian, et al., Ed.,Principles of Bone Biology, San Diego: Academic Press).

Daily dosage ranges for bone resorption inhibitors, osteoanabolic agentsand other agents which can be used to benefit the skeleton when used incombination with a compound of structural formula I are those which areknown in the art. In such combinations, generally the daily dosage rangefor the SARMs of structural formula I ranges from about 0.01 to about1000 mg per adult human per day, such as for example, from about 0.1 toabout 200 mg/day. However, adjustments to decrease the dose of eachagent can be made due to the increased efficacy of the combined agent.

In particular, when a bisphosphonate is employed, dosages from about 2.5to about 100 mg/day (measured as the free bisphosphonic acid) areappropriate for treatment, such as for example ranging from 5 to 20mg/day, or about 10 mg/day. Prophylactically, doses of about 2.5 toabout 10 mg/day and especially about 5 mg/day should be employed. Forreduction in side-effects, it can be desirable to administer thecombination of a compound of structural formula I and the bisphosphonateonce a week. For once weekly administration, doses ranging from about 15mg to about 700 mg per week of bisphosphonate and from about 0.07 toabout 7000 mg of a compound of structural formula I can be employed,either separately, or in a combined dosage form. A compound ofstructural formula I can be favorably administered in acontrolled-release delivery device, particularly for once weeklyadministration.

For the treatment of atherosclerosis, hypercholesterolemia, andhyperlipidemia, the compounds of structural formula I can be effectivelyadministered in combination with one or more additional active agents.The additional active agent or agents can be chosen from lipid-alteringcompounds such as HMG-CoA reductase inhibitors, agents having otherpharmaceutical activities, and agents that have both lipid-alteringeffects and other pharmaceutical activities. Non-limiting examples ofHMG-CoA reductase inhibitors include statins in their lactonized ordihydroxy open acid forms and pharmaceutically acceptable salts andesters thereof, including but not limited to lovastatin (see U.S. Pat.No. 4,342,767); simvastatin (see U.S. Pat. No. 4,444,784); dihydroxyopen-acid simvastatin, particularly the ammonium or calcium saltsthereof; pravastatin, particularly the sodium salt thereof (see U.S.Pat. No. 4,346,227); fluvastatin, particularly the sodium salt thereof(see U.S. Pat. No. 5,354,772); atorvastatin, particularly the calciumsalt thereof (see U.S. Pat. No. 5,273,995); cerivastatin, particularlythe sodium salt thereof (see U.S. Pat. No. 5,177,080), and nisvastatin,also referred to as NK-104 (see PCT international applicationpublication number WO 97/23200).

Additional active agents which can be employed in combination with acompound of structural formula I include, but are not limited to,HMG-CoA synthase inhibitors; squalene epoxidase inhibitors; squalenesynthetase inhibitors (also known as squalene synthase inhibitors),acyl-coenzyme A: cholesterol acyltransferase (ACAT) inhibitors includingselective inhibitors of ACAT-1 or ACAT-2 as well as dual inhibitors ofACAT-1 and -2; microsomal triglyceride transfer protein (MTP)inhibitors; probucol; niacin; cholesterol absorption inhibitors, such asSCH-58235, also known as ezetimibe and1-(4-fluorophenyl)-3(R)-[3(S)-(4-fluorophenyl)-3-hydroxypropyl)]-4(S)-(4-hydroxyphenyl)-2-azetidinone,which is described in U.S. Pat. Nos. 5,767,115 and 5,846,966; bile acidsequestrants; LDL (low density lipoprotein) receptor inducers; plateletaggregation inhibitors, for example glycoprotein IIb/IIIa fibrinogenreceptor antagonists and aspirin; human peroxisome proliferatoractivated receptor gamma (PPAR□), agonists, including the compoundscommonly referred to as glitazones, for example troglitazone,pioglitazone and rosiglitazone and thiazolidinediones as well as thosePPAR□. Other compounds which can be utilized are PPARα agonists, such asclofibrate, fenofibrate including micronized fenofibrate, andgemfibrozil; PPAR dual α/γ agonists; vitamin B₆ (also known aspyridoxine) and the pharmaceutically acceptable salts thereof such asthe HCl salt; vitamin B₁₂ (also known as cyanocobalamin); folic acid ora pharmaceutically acceptable salt or ester thereof such as the sodiumsalt and the methylglucamine salt; anti-oxidant vitamins such as vitaminC and E and beta carotene; beta-blockers; angiotensin II antagonistssuch as losartan; angiotensin converting enzyme inhibitors, such asenalapril and captopril; calcium channel blockers, such as nifedipineand diltiazem; endothelin antagonists; agents such as LXR ligands thatenhance ABC1 gene expression; bisphosphonate compounds, such asalendronate sodium; and cyclooxygenase-2 inhibitors, such as rofecoxiband celecoxib, as well as other agents known to be useful in thetreatment of these conditions.

Daily dosage ranges for the above-mentioned compounds which can beemployed in combination with the compounds of the present inventioncorrespond to those which are known in the art, although due to thecombined action with the compounds of structural formula I, the dosagecan be somewhat lower when administered in combination.

One embodiment of the invention is a method for affecting a boneturnover marker in a mammal comprising administering a therapeuticallyeffective amount of a compound according to formula I. Non-limitingexamples of bone turnover markers can be selected from urinaryC-telopeptide degradation products of type I collagen (CTX), urinaryN-telopeptide cross-links of type I collagen (NTX), osteocalcin (boneGla protein), dual energy x-ray absorptionmetry (DXA), bone specificalkaline phosphatase (BSAP), quantitative ultrasound (QUS), anddeoxypyridinoline (DPD) crosslinks.

In accordance with the method of the present invention, the individualcomponents of the combination can be administered separately atdifferent times during the course of therapy or concurrently in dividedor single combination forms. The instant invention is therefore to beunderstood as embracing all such regimes of simultaneous or alternatingtreatment and the term “administering” is to be interpreted accordingly.It will be understood that the scope of combinations of the compounds ofthis invention with other agents useful for treating diseases caused byandrogen deficiency or that can be ameliorated by addition of androgen.

Abbreviations Used in the Description of the Preparation of theCompounds of the Present Invention: DHT Dihydrotestosterone DIPEADiisopropylethylamine DMEM Dulbecceo modified eagle media DMSO Dimethylsulfoxide DMF N,N-Dimethylformamide EDC1-(3-Dimethylaminopropyl)3-ethylcarbodiimide HCl EDTAEthylenediaminetetraacetic acid EtOH Ethanol EtOAc Ethyl acetate FCSFetal calf serum HEPES (2-Hydroxyethyl)-1-piperazineethanesulfonic acidHOAt 1-hydroxy-7-azabenzotriazole HPLC High-performance liquidchromatography MeOH Methanol MgSO₄ Magnesium sulfate RT or rt Roomtemperature TFA Trifluoroacetic acid

The compounds of this invention may be prepared by employing reactionsas shown in the following schemes, in addition to other standardmanipulations that are known in the literature or exemplified in theexperimental procedures. The illustrative schemes below, therefore, arenot limited by the compounds listed or by any particular substitutentsemployed for illustrative purposes. Substituent numbering as shown inthe schemes does not necessarily correlate to that used in the claimsand often, for clarity, a single substituent is shown attached to thecompound in place of multiple substituents which are allowed under thedefinitions of Formula I defined previously.

Schemes A-C provide general guidelines for making compounds of FormulaI. Scheme A illustrates the addition of the amide, HNR¹R², as well asthe formation of the fused ring system starting from the 4-azasteroidalbackbone having an unsubstituted 2-position carbon. Scheme B illustratesan alternative addition route to add the amide, HNR¹R², on thefused4-azasteroidal backbone. Scheme C illustrates the addition of theamide, HNR¹R², as well as the formation of the fused ring systemstarting from the 4-azasteroidal backbone having a saturated 2-positioncarbon. In the synthesizing compounds of formulas A-5, B-2, and C-5various commercially available amines can be used.

EXAMPLE 1

Step A:

Ethyl (5aR,5bS, 7aS, 8R, 10aS,10bS)-5b,6,7,7a,8,9,10,10a,10b,11,12,12a-dodecahydro-5aH-imidazo[1,2-a]indeno[5,4-f]quinoline-8-carboxylate(1-b)

To a stirred suspension of 1-a (5.0 g, 15 mmol) (J. Med. Chem. 292298-2315 (1986)) in anhydrous CH₂Cl₂/mesitylene (1:2; 60 mL) was addedTiCl₄ (60 mmol, 1N in CH₂Cl₂). The mixture was refluxed at 140 ° C. for20 minutes then removed from heat and briefly air cooled.Aminoacetaldehyde diethyl acetal (12.0 g, 90 mmol) in 10 mL CH₂Cl₂ wasadded slowly with stirring. The resulting solution was refluxed at 140 °C. for 4 hours as CH₂Cl₂ was collected in a self-pressurizing additionfunnel. The reaction mixture was then cooled to RT, neutralized withsaturated aqueous sodium bicarbonate, and concentrated to dryness invacuo. The solid residue was suspended in CH₂Cl₂ (200 mL). After 30minutes of stirring, the suspension was filtered through a pad of celiteand the filtrate was concentrated in vacuo. The residue was dissolved inMeOH (20 mL) and acidified to pH=2 with 1 N HCl, then 200 mL water wasadded and extracted by EtOAc (75 mL, ×2). The acidic aqueous layer wasadjusted to pH=12 with 1 N NaOH. A large amount of solid precipitatedand was filtered. The precipitate was dissolved in EtOAc and dried overMgSO₄. Drying agent was filtered and the filtrate was concentrated invacuo to obtain the title compound 1-b as a beige solid. ¹H-NMR (CD₃OD);δ0.71 (s, 3H), 0.79 (s, 3H), 1.13-1.58 (m, 7H), 1.25 (t, 3H), 1.72-1.95(m, 5H), 2.07-2.15 (m, 2H), 2.31-2.34 (m, 1H), 2.41 (t, 1H), 3.74 (dd,1H), 4.06-4.19 (m, 2H), 6.40 (d, 1H), 6.47 (d, 1l), 6.96 (s, 1H), 7.13(s, 1H). Measured [M+H]=369.0.

Step B:

(5aR,5bS, 7aS, 8R, 10aS, 10bS)-5b,6,7,7a,8,9,10,10a,10b,11,12,12a-dodecahydro-5aH-imidazo[1,2-a]indeno[5,4-f]quinoline-8-carboxylicacid (1-c)

To a stirred solution of 1-b (9.0 g, 25 mmol) in MeOH (20 mL) was added3N NaOH (75 mmol). The resulting solution was heated in a microwavereactor (150 watts) at 100° C. for 60 minutes. While still basic, thereaction mixture was diluted with water (75 mL) and extracted with ethylacetate (50 mL ×2). The aqueous layer was then carefully neutralized topH=6 with 3 N HCl to afford a large amount of solid precipitate. Afterfiltration, the solid was collected as the desired product 1-c. Thefiltrate was subsequently concentrated and dissolved in MeOH (30 mL).Upon filtration, the solution was dried over MgSO₄ and concentrated toyield 2^(nd) crop of the desired product 1-c as a white solid. 1H-NMR(CD₃OD); □ 0.77 (s, 3H), 0.876 (s, 3H), 1.19-1.65 (m, 71), 1.74-2.17 (m,7H), 2.40-2.46 (m, 2H), 4.05 (dd, 1H), 6.62 (d, 1H), 7.02 (d, 1H), 7.50(s, 1H), 7.60(s, 1H). Measured [M+H]=340.9.

Step C:

N-(2,6-dichloropyridin-3-yl)-(5aR,5bS, 7aS, 8R, 10aS,10bS)5b,6,7,7a,8,9,10,10a,10b,11,12,12a-dodecahydro-5aH-imidazo[1,2-a]indeno[5,4-f]quinoline-8-carboxamide(1-1)

To a stirred solution of 1-c (0.35 g, 1 mmol) in anhydrous CH₂Cl₂ (1 mL)at 0° C. was added anhydrous DMF (catalytic) and thionyl chloride (0.18g, 1.5 mmol). The resulting solution was warmed to ambient temperatureand stirred for 1 hour. Anhydrous toluene (5 mL, ×2) was added andconcentrated in vacuo at ambient temperature to give a yellow orange oilwhich was dissolved in anhydrous CH₂Cl₂(1 mL). DIPEA (2 mmol) and 1-d(1.5 mmol) were added. The mixture was stirred at ambient temperaturefor 5 minutes and then heated in a microwave reactor at 80° C. for 10minutes. Upon removal of the solvent, the residue was purified onreversed phase HPLC (5% CH₃CN/95% H₂O with 0.1% TFA to 80% CH₃CN/20% H₂Owith 0.1% TFA over 20 minutes) to give the title compound 1-1. ¹H-NMR(CD₃OD); δ 0.79 (s, 3H), 0.89 (s, 3H), 1.21-1.28 (m, 1H), 1.29-1.44 (m,3H), 1.53-1.64 (m, 3H), 1.81-2.04 (m, 6H), 2.15-2.26 (m, 2H), 2.45-2.48(m, 1H), 2.64 (t, 1H), 6.66 (d, 1H), 7.07 (d, 1H), 7.43 (d, 1H), 7.54(d, 1H), 7.65 (d, 1H), 8.27 (d, 1H). Measured [M+H] 450.3115.

Examples 1-2 to 1-45 in Table 1 were prepared in a similar manner ascompound (1-1), but using the appropriate amine to generate the finaldesired acetamide.

TABLE 1

Mass spectrum Measured Ex. NR¹R² Name [M + H] 1-1

N-(2,6-dichloropyridin-3-yl)-(5aR,5bS,7aS, 8R, 10aS,10bS)-5b,6,7,7a,8,9,10,10a,10b,11,12,12a-dodecahydro-5aH-imidazol[1,2-a]indeno[5,4-f]quinoline-8-carboxamide450.3115 1-2

N-(2-cyano-3-fluorophenyl)-(5aR,5bS,7aS, 8R, 10aS,10bS)-5b,6,7,7a,8,9,10,10a,10b,11,12,12a-dodecahydro-5aH-imidazo[1,2-a]indeno[5,4-f]quinoline-8-carboxamide459.2566 1-3

N--(2-cyano-3-chlorophenyl)-(5aR,5bS,7aS, 8R, 10aS,10bS)-5b,6,7,7a,8,9,10,10a,10b,11,12,12a-dodecahydro-5aH-imidazol[1,2-a]indeno[5,4-f]quinoline-8-carboxamide475.2278 1-4

N-(2-cyano-4-chlorophenyl)-(5aR,5bS,7aS, 8R, 10aS,10bS)-5b,6,7,7a,8,9,10,10a,10b,11,12,12a-dodecahydro-5aH-imidazol[1,2-a]indeno[5,4-f]quinoline-8-carboxamide475.2291 1-5

N--(2-cyano-3-methylphenyl)-(5aR,5bS,7aS, 8R, 10aS,10bS)-5b,6,7,7a,8,9,10,10a,10b,11,12,12a-dodecahydro-5aH-imidazol[1,2-a]indeno[5,4-f]quinoline-8-carboxamide455.2825 1-6

N--(2-chlorophenyl)-(5aR,5bS, 7aS, 8R,10aS,10bS)-5b,6,7,7a,8,9,10,10a,10b,11,12,12a-dodecahydro-5aH-imidazo[1,2-a]indeno[5,4-f]quinoline-8-carboxamide450.232 1-7

N--(2-cyano-5-methylphenyl)-(5aR,5bS,7aS, 8R, 10aS,10bS)-5b,6,7,7a,8,9,10,10a,10b,11,12,12a-dodecahydro-5aH-imidazol[1,2-a]indeno[5,4-f]quinoline-8-carboxamide455.2822 1-8

N--(3-chlorophenyl)-(5aR,5bS, 7aS, 8R,10aS,10bS)-5b,6,7,7a,8,9,10,10a,10b,11,12,12a-dodecahydro-5aH-imidazo[1,2-a]indeno[5,4-f]quinoline-8-carboxamide450.2323 1-9

N--(2,6-dichlorophenyl)-(5aR,5bS, 7aS, 8R, 10aS,10bS)-5b,6,7,7a,8,9,10,10a,10b,11,12,12a-dodecahydro-5aH-imidazo[1,2-a]indeno[5,4-f]quinoline-8-carboxamide484.1931 1-10

N--(2-fluorophenyl)-(5aR,5bS, 7aS, 8R,10aS,10bS)-5b,6,7,7a,8,9,10,10a,10b,11,12,12a-dodecahydro-5aH-imidazo[1,2-a]indeno[5,4-f]quinoline-8-carboxamide434.2609 1-11

N--(3-fluorophenyl)-(5aR,5bS, 7aS, 8R,10aS,10bS)-5b,6,7,7a,8,9,10,10a,10b,11,12,12a-dodecahydro-5aH-imidazo[1,2-a]indeno[5,4-f]quinoline-8-carboxamide434.2609 1-12

N-Benzyl-(5aR,5bS, 7aS, 8R,10aS,10bS)-5b,6,7,7a,8,9,10,10a,10b,11,12,12a-dodecahydro-5aH-imidazo[1,2-a]indeno[5,4-f]quinoline-8-carboxamide430.2844 1-13

N-(1-phenylethyl)-(5aR,5bS, 7aS, 8R,10aS,10bS)-5b,6,7,7a,8,9,10,10a,10b,11,12,12a-dodecahydro-5aH-imidazo[1,2-a]indeno[5,4-f]quinoline-8-carboxamide444.3002 1-14

N--[(1-(2-chlorophenyl)ethyl]-(5aR,5bS,7aS, 8R, 10aS,10bS)-5b,6,7,7a,8,9,10,10a,10b,11,12,12a-dodecahydro-5aH-imidazo[1,2-a]indeno[5,4-f]quinoline-8-carboxamide464.2464 1-15

N-[(1-(3-chlorophenyl)ethyl]-(5aR,5bS,7aS, 8R, 10aS,10bS)-5b,6,7,7a,8,9,10,10a,10b,11,12,12a-dodecahydro-5aH-imidazo[1,2-a]indeno[5,4-f]quinoline-8-carboxamide464.2465 1-16

N-[(1-(2,6-dichlorophenyl)ethyl]-(5aR,5bS, 7aS, 8R, 10aS,10bS)-5b,6,7,7a,8,9,10,10a,10b,11,12,12a-dodecahydro-5aH-imidazo[1,2-a]indeno[5,4-f]quinoline-8-carboxamide498.208 1-17

N-[1-(1,3-benzodioxol-5-yl)ethyl]-(5aR,5bS, 7aS, 8R, 10aS,10bS)-5b,6,7,7a,8,9,10,10a,10b,11,12,12a-dodecahydro-5aH-imidazo[1,2-a]indeno[5,4-f]quinoline-8-carboxamide474.2747 1-18

N-[(1H-imidazol-2-yl)methyl]-(5aR,5bS,7aS, 8R, 10aS,10bS)-5b,6,7,7a,8,9,10,10a,10b,11,12,12a-dodecahydro-5aH-imidazo[1,2-a]indeno[5,4-f]quinoline-8-carboxamide420.2766 1-19

N-[(4-methyl-1H-imidazol-2-yl)methyl]-((5aR,5bS, 7aS, 8R, 10aS,10bS)-5b,6,7,7a,8,9,10,10a,10b,11,12,12a-dodecahydro-5aH-imidazo[1,2-a]indeno[5,4-f]quinoline-8-carboxamide434.292 1-20

N-(1H-benzimidazol-2-ylmethyl)-(5aR,5Bs, 7aS, 8R, 10aS,10bS)-5b,6,7,7a,8,9,10,10a,10b,11,12,12a-dodecahydro-5aH-imidazo[1,2-a]indeno[5,4-f]quinoline-8-carboxamide470.2915 1-21

N-(5-methoxy-1H-benzimidazol-2-ylmethyl)-( (5aR,5bS, 7aS, 8R,10aS,10bS)-5b,6,7,7a,8,9,10,10a,10b,11,12,12a-dodecahydro-5aH-imidazo[1,2-a]indeno[5,4-f]quinoline-8-carboxamide500.3032 1-22

N-(2-fluorobenzyl)-(5aR,5bS, 7aS, 8R,10aS,10bS)-5b,6,7,7a,8,9,10,10a,10b,11,12,12a-dodecahydro-5aH-imidazo[1,2-a]indeno[5,4-f]quinoline-8-carboxamide448.2763 1-23

N-(3-fluorobenzyl)-(5aR,5bS, 7aS, 8R,10aS,10bS)-5b,6,7,7a,8,9,10,10a,10b,11,12,12a-dodecahydro-5aH-imidazo[1,2-a]indeno[5,4-f]quinoline-8-carboxamide448.2765 1-24

N-(4-fluorobenzyl)-(5aR,5bS, 7aS, 8R,10aS,10bS)-5b,6,7,7a,8,9,10,10a,10b,11,12,12a-dodecahydro-5aH-imidazo[1,2-a]indeno[5,4-f]quinoline-8-carboxamide448.2767 1-25

N--(2,6-difluorobenzyl)-(5aR,5bS, 7aS,8R, 10aS,10bS)-5b,6,7,7a,8,9,10,10a,10b,11,12,12a-dodecahydro-5aH-imidazo[1,2-a]indeno[5,4-f]quinoline-8-carboxamide466.2668 1-26

N-(pyridin-2-ylmethyl)-(5aR,5bS, 7aS,8R, 10aS,10bS)-5b,6,7,7a,8,9,10,10a,10b,11,12,12a-dodecahydro-5aH-imidazo[1,2-a]indeno[5,4-f]quinoline-8-carboxamide431.2815 1-27

N--(pyridin-3-ylmethyl)-(5aR,5bS, 7aS,8R, 10aS,10bS)-5b,6,7,7a,8,9,10,10a,10b,11,12,12a-dodecahydro-5aH-imidazo[1,2-a]indeno[5,4-f]quinoline-8-carboxamide431.2818 1-28

N-(pyridin-4-ylmethyl)-(5aR,5bS, 7aS,8R, 10aS,10bS)-5b,6,7,7a,8,9,10,10a,10b,11,12,12a-dodecahydro-5aH-imidazo[1,2-a]indeno[5,4-f]quinoline-8-carboxamide431.282 1-29

N-(2-methylbenzyl)-(5aR,5bS, 7aS, 8R,10aS,10bS)-5b,6,7,7a,8,9,10,10a,10b,11,12,12a-dodecahydro-5aH-imidazo[1,2-a]indeno[5,4-f]quinoline-8-carboxamide444.3028 1-30

N-(3-methylbenzyl)-(5aR,5bS, 7aS, 8R,10aS,10bS)-5b,6,7,7a,8,9,10,10a,10b,11,12,12a-dodecahydro-5aH-imidazo[1,2-a]indeno[5,4-f]quinoline-8-carboxamide444.3028 1-31

N--(4-methylbenzyl)-(5aR,5bS, 7aS, 8R,10aS,10bS)-5b,6,7,7a,8,9,10,10a,10b,11,12,12a-dodecahydro-5aH-imidazo[1,2-a]indeno[5,4-f]quinoline-8-carboxamide444.303 1-32

N-(1R,1-phenylpropyl)-(5aR,5bS, 7aS,8R, 10aS,10bS)-5b,6,7,7a,8,9,10,10a,10b,11,12,12a-dodecahydro-5aH-imidazo[1,2-a]indeno[5,4-f]quinoline-8-carboxamide458.3193 1-33

N--(1S,1-phenylpropyl)-(5aR,5bS, 7aS,8R, 10aS,10bS)-5b,6,7,7a,8,9,10,10a,10b,11,12,12a-dodecahydro-5aH-imidazo[1,2-a]indeno[5,4-f]quinoline-8-carboxamide458.3188 1-34

N-(1H-imidazo[4,5-b]pyridin-2-ylmethyl)-(5aR,5bS, 7aS, 8R,10aS,10bS)-5b,6,7,7a,8,9,10,10a,10b,11,12,12a-dodecahydro-5aH-imidazo[1,2-a]indeno[5,4-f]quinoline-8-carboxamide471.2878 1-35

N-[(4-methylthio-1H-imidazol-2-yl)methyl]-(5aR,5bS, 7aS, 8R,10aS,10bS)-5b,6,7,7a,8,9,10,10a,10b,11,12,12a-dodecahydro-5aH-imidazo[1,2-a]indeno[5,4-f]quinoline-8-carboxamide470.2057 1-36

N-(2-chloro-4-cyanophenyl)-(5aR,5bS,7aS, 8R, 10aS,10bS)-5b,6,7,7a,8,9,10,10a,10b,11,12,12a-dodecahydro-5aH-imidazo[1,2-a]indeno[5,4-f]quinoline-8-carboxamide475.1 1-37

N-(3,5-dichloropyridin-2-yl)-(5aR,5bS,7aS, 8R, 10aS,10bS)-5b,6,7,7a,8,9,10,10a,10b,11,12,12a-dodecahydro-5aH-imidazo[1,2-a]indeno[5,4-f]quinoline-8-carboxamide485.04 1-38

N-(4-chloropyridin-3-yl)-(5aR,5bS, 7aS,8R, 10aS,10bS)-5b,6,7,7a,8,9,10,10a,10b,11,12,12a-dodecahydro-5aH-imidazo[1,2-a]indeno[5,4-f]quinoline-8-carboxamide451.15 1-39

N-(2-chloropyridin-3-yl)-(5aR,5bS, 7aS,8R, 10aS,10bS)-5b,6,7,7a,8,9,10,10a,10b,11,12,12a-dodecahydro-5aH-imidazo[1,2-a]indeno[5,4-f]quinoline-8-carboxamide451.17 1-40

N--(2-chloropyridin-5-yl)-(5aR,5bS, 7aS,8R, 10aS,10bS)-5b,6,7,7a,8,9,10,10a,10b,11,12,12a-dodecahydro-5aH-imidazo[1,2-a]indeno[5,4-f]quinoline-8-carboxamide451.17 1-41

N-[1-(pyridin-2-yl)ethyl]-(5aR,5bS, 7aS,8R, 10aS,10bS)-5b,6,7,7a,8,9,10,10a,10b,11,12,12a-dodecahydro-5aH-imidazo[1,2-a]indeno[5,4-f]quinoline-8-carboxamide445.0 1-42

N--[1-(pyridin-3-yl)ethyl]-(5aR,5bS, 7aS,8R, 10aS,10bS)-5b,6,7,7a,8,9,10,10a,10b,11,12,12a-dodecahydro-5aH-imidazo[1,2-a]indeno[5,4-f]quinoline-8-carboxamide446.0 1-43

N-[1-(pyridin-4-yl)ethyl]-(5aR,5bS, 7aS,8R, 10aS,10bS)-5b,6,7,7a,8,9,10,10a,10b,11,12,12a-dodecahydro-5aH-imidazo[1,2-a]indeno[5,4-f]quinoline-8-carboxamide445.0 1-44

N-(primidin-4-yl)-(5aR,5bS, 7aS, 8R,10aS,10bS)-5b,6,7,7a,8,9,10,10a,10b,11,12,12a-dodecahydro-5aH-imidazo[1,2-a]indeno[5,4-f]quinoline-8-carboxamide417.9 1-45

N--(5-cyanoprimidin-4-yl)-(5aR,5bS, 7aS,8R, 10aS,10bS)-5b,6,7,7a,8,9,10,10a,10b,11,12,12a-dodecahydro-5aH-imidazo[1,2-a]indeno[5,4-f]quinoline-8-carboxamide442.9

EXAMPLE 2

Step A:

Methyl 2-{[(5aR,5bS, 7aS, 8R, 10aS,10bS)-5,5a,5b,6,7,7a,8,9,10,10a,10b,11,12,12a-tetradecahydro-4H-imidazo[1,2-a]indeno[5,4-f]quinolin-8-ylcarbonyl]amino}butanoate(2-1)

To a stirred solution of 1-c (0.1 g, 0.3 mmol) in DMF (2 mL) was addedEDC (0.08 g, 0.44 mmol), HOAt (0.045 g, 0.3 mmol), DIPEA (0.151 g, 1.2mmol), and 2-a (1.5 mmol). The resulting mixture was heated in amicrowave reactor (150 watts) at 100° C. for 30 minutes. Upon removal ofthe solvent, the reaction mixture was purified by reversed phase BPLC toafford the title compound 2-1. ¹H-NMR (CD₃OD); δ 0.75 (d, 3H), 0.90 (d,3H), 0.97-1.02 (m, 3H), 1.24-1.42 (m, 4H), 1.52-1.65 (m, 3H), 1.72-2.05(m, 8H), 2.13-2.17 (m, 1H), 2.39-2.49 (m, 2H), 3.72 (d, 3H), 4.09-4.12(m, 1H), 4.30-4.34 (m, 1H), 6.67 (d, 1H), 7.09 (m, 1H), 7.56 (d, 1H),7.66(d, 1H). Measured [M+H]=439.9.

Examples 2-2 to 2-11 in Table 2 were prepared in a similar manner ascompound (2-1), but using the appropriate amine to generate the finaldesired acetamide.

TABLE 2

Mass spectrum Measured Ex. NR¹R² Name [M + H] 2-1

Methyl2-{[(5aR,5bS,7aS,8R,10aS,10bS)-5,5a,5b,6,7,7a,8,9,10,10a,10b,11,12,12a-tetradecahydro-4H-imidazo[1,2-a]indeno[5,4-f]quinolin-8-ylcarbonyl]amino}butanoate439.9 2-2

N-[(1S)-1-(aminocarbonyl)propyl]-(5aR,5bS, 7aS, 8R, 10aS,10bS)-5b,6,7,7a,8,9,10,10a,10b,11,12,12a-dodecahydro-5aH-imidazo[1,2-a]indeno[5,4-f]quinoline-8-carboxamide396.9 2-3

N-[(1S)-1-(methylaminocarbonyl)propyl](5aR,5bS, 7aS, 8R, 10aS,10bS)-5b,6,7,7a,8,9,10,10a,10b,11,12,12a-dodecahydro-5aH-imidazo[1,2-a]indeno[5,4-f]quinoline-8-carboxamide439.15 2-4

N-[(1S)-1-(dimethylaminocarbonyl)propyl](5aR,5bS, 7aS, 8R, 10aS,10bS)-5b,6,7,7a,8,9,10,10a,10b,11,12,12a-dodecahydro-5aH-imidazo[1,2-a]indeno[5,4-f]quinoline-8-carboxamide453.18 2-5

N-(2,2,2-trifluoroethyl)-(5aR,5bS, 7aS, 8R,10aS,10bS)-5b,6,7,7a,8,9,10,10a,10b,11,12,12a-dodecahydro-5aH-imidazo[1,2-a]indeno[5,4-f]quinoline-8-carboxamide421.9 2-6

N-(3,3,3-trifluoropropyl)-(5aR,5bS, 7aS,8R, 10aS,10bS)-5b,6,7,7a,8,9,10,10a,10b,11,12,12a-dodecahydro-5aH-imidazo[1,2-a]indeno[5,4-f]quinoline-8-carboxamide435.9 2-7

N-[4-(cyanomethyl)phenyl]-(5aR,5bS,7aS, 8R, 10aS,10bS)-5b,6,7,7a,8,9,10,10a,10b,11,12,12a-dodecahydro-5aH-imidazo[1,2-a]indeno[5,4-f]quinoline-8-carboxamide455.0 2-8

Methyl4-{[(5aR,5bS,7aS,8R,10aS,10bS)-5b,6,7,7a,8,9,10,10a,10b,11,12,12a-dodecahydro-5aH-imidazo[1,2-a]indeno[5,4-f]quinolin-8-ylcarbonyl]amino}benzoate473.9 2-9

N-[4-(aminocarbonyl)phenyl]-(5aR,5bS,7aS,8R,10aS,10bS)-5b,6,7,7a,8,9,10,10a,10b,11,12,12a-dodecahydro-5aH-imidazo[1,2-a]indeno[5,4-f]quinoline-8-carboxamide458.9 2-10

(5aR,5bS,7aS,8R,10aS,10bS)-N-[4-(1,2,3-thiadiazol-4-yl)phenyl]-5b,6,7,7a,8,9,10,10a,10b,11,12,12a-dodecahydro-5aH-imidazo[1,2-a]indeno[5,4-f]quinoline-8-carboxamide499.9 2-11

(5aR,5bS,7aS,8R,10aS,10bS)-N-(1H-indazol-6-yl)-5b,6,7,7a,8,9,10,10a,10b,11,12,12a-dodecahydro-5aH-imidazo[1,2-a]indeno[5,4-f]quinoline-8-carboxamide455.9

EXAMPLE 3

Step A:

Methyl (5aR,5bS, 7aS, 8R, 10aS,10bS)-5,5a,5b,6,7,7a,8,9,10,10a,10b,11,12,12a-tetradecahydro-4H-imidazo[1,2-a]indeno[5,4-f]quinoline-8-carboxylate(3-b)

To a stirred suspension of 3-a (5.0 g, 15 mmol)(J. Med. Chem. 292298-2315 (1986)) in anhydrous CH₂Cl₂/mesitylene (1:2; 60 mL) was addedTiCl₄ (6.0 mmol, 1N in CH₂Cl₂). The mixture was refluxed at 140° C. for20 minutes then removed from heat and briefly air cooled.Aminoacetaldehyde diethyl acetal (12.0 g, 90 mmol) in 10 mL CH₂Cl₂ wasadded slowly with stirring. The resulting solution was refluxed at 140°C. for 4 hours as CH₂Cl₂ was collected in a self-pressurizing additionfunnel. The reaction mixture was then cooled to ambient temperature,neutralized with saturated aqueous sodium bicarbonate, and concentratedto dryness in vacuo. The solid residue was suspended in CH₂Cl₂ (200 mL).After 30 minutes of stirring, the suspension was filtered through a padof celite and the filtrate was concentrated in vacuo. The residue wasdissolved in MeOH (20 mL) and acidified to pH=2 with 1 N HCl. Afteraddition of 200 mL water, the mixture was extracted by EtOAc (75 mL,×2). The acidic aqueous layer was adjusted to pH=12 with 1 N NaOH. Alarge amount of solid precipitated and was collected by filtration andwas subsequently dissolved in EtOAc and dried over MgSO₄. Upon removalof the solvent, the title compound 3-b was obtained as a beige solid.¹H-NMR (CD₃OD); δ 0.69 (s, 3H), 0.78 (s, 3H), 1.02 (dt, 1H), 1.13-1.46(m, 5H), 1.50-1.58 (m, 211), 1.62-1.94 (m, 5H), 2.03-2.15 (m, 3H),2.27-2.32 (m, 1H), 2.40-2.44 (t, 1H), 2.78-2.93 (m, 2H), 3.61 (dd, 1H),3.65 (s, 3H), 6.87 (s, 1H), 7.02 (s, 1H). Measured [M+H]=357.0.

Step B:

(5aR,5bS, 7aS, 8R, 10aS, 10bS)-5,5a,5b,6,7,7a,8,9,10,10a,10b,11,12,12a-tetradecahydro-4H-imidazo[1,2-a]indeno[5,4-f]quinoline-8-carboxylicacid (3-c)

To a stirred solution of 3-b (9.0 g, 25 mmol) in MeOH (20 mL) was added3 N NaOH (75 mmol). The resulting solution was heated in a microwavereactor (150 watts) at 100° C. for 60 minutes. While still basic, thereaction mixture was diluted with water (75 mL) and extracted with ethylacetate (50 mL ×2). The aqueous layer was carefully acidified to pH=6with 3 N HCl to yield a large amount of solid precipitate. Afterfiltration the solid was collected and dried to yield the title compound3-c as a white solid. The filtrate was concentrated to dryness anddissolved in MeOH (30 mL). Upon filtration, the MeOH filtrate wasconcentrated in vacuo to yield a 2^(nd) crop of the title compound 3-cas a white solid. ¹H-NMR (CD₃OD); δ 0.75 (s, 3H), 0.84 (s, 3H),1.06-1.11 (dt, 1H), 1.18-1.27 (m, 2H), 1.30-1.38 (m, 2H), 1.41-1.50 (m,1H), 1.55-1.86 (m, 6H), 1.97-2.01 (m, 1H), 2.06-2.13 (m, 2H), 2.20-2.24(m, 1H), 2.38-2.45 (m, 2H), 3.02-3.18 (m, 2H), 3.87 (dd, 1H), 7.46 (d,1H), 7.52 (d, 1H). Measured [M+H]=343.38.

Step C:

N-(2,6-dichlorophenyl)-(5aR,5bS, 7aS, 8R, 10aS,10bS)5,5a,5b6,7,7a,8,9,10,10a,10b,11,12,12a-tetradecahydro-4H-imidazo[1,2-a]indeno[5,4-f]quinoline-8-carboxamide(3-1)

To a stirred solution of 3-c (0.35 g, 1 mmol) in anhydrous CH₂Cl₂ (1 ml)at 0° C. was added anhydrous DMF (catalytic) and thionyl chloride (0.18g, 1.5 mmol). The resulting solution was warmed to ambient temperatureand stirred for 1 hour. Anhydrous toluene (5 mL ×2) was added andconcentrated in vacuo at ambient temperature to give a yellow orange oilwhich was dissolved in anhydrous CH₂Cl₂(1 mL). DIPEA (2 mmol), and 3-d(1.5 mmol), were added. The mixture was stirred at ambient temperaturefor 5 minutes and then heated in microwave reactor (150 watts) at 80° C.for 10 minutes. Upon removal of the solvent, the residue was purified onreversed phase HPLC (5% CH₃CN/95% H₂O with 0.1% TFA to 80% CH₃CN/20% H₂Owith 0.1% TFA) to give the title compound 3-1. ¹H-NMR (CD₃OD); δ 0.85(s, 3H), 0.87 (s, 3H), 1.11 (m, 1H), 1.21-1.94 (m, 11H), 1.98-2.02 (m,1H), 2.20-2.33 (m, 3H), 2.40-2.43 (m, 1H), 2.56 (t, 1H), 2.99-3.16 (m,2H), 3.84 (dd, 1H), 7.29 (m, 1H), 7.38 (d, 1H), 7.45-7.47 (m, 3H).Measured [M+H]=486.17.

Examples 3-2 to 3-19 in Table 3 were prepared in a similar manner ascompound (3-1), but using the appropriate amine to generate the finaldesired acetamide.

TABLE 3

Mass spectrum Measured Ex. NR¹R² Name [M + H] 3-1

N-(2,6-dichlorophenyl)-(5aR,5bS, 7aS,8R, 10aS,10bS)-5,5a,5b6,7,7a,8,9,10,10a,10b,11,12,12a-tetradecahydro-4H-imidazo[1,2-a]indeno[5,4-f]quinoline-8-carboxamide486.17 3-2

N-(2-cyanophenyl)-(5aR,5bS, 7aS, 8R,10aS,10bS)-5,5a,5b6,7,7a,8,9,10,10a,10b,11,12,12a-tetradecahydro-4H-imidazo[1,2-a]indeno[5,4-f]quinoline-8-carboxamide443.1 3-3

N-(2-methyl-4-cyanophenyl)-(5aR,5bS,7aS, 8R, 10aS,10bS)-5,5a,5b6,7,7a,8,9,10,10a,10b,11,12,12a-tetradecahydro-4H-imidazo[1,2-a]indeno[5,4-f]quinoline-8-carboxamide457.2949 3-4

N-benzyl-(5aR,5bS, 7aS, 8R,10aS,10bS)-5,5a,5b6,7,7a,8,9,10,10a,10b,11,12,12a-tetradecahydro-4H-imidazo[1,2-a]indeno[5,4-f]quinoline-8-carboxamide432.3008 3-5

N-(3-chlorobenzyl)-(5aR,5bS, 7aS, 8R,10aS,10bS)-5,5a,5b6,7,7a,8,9,10,10a,10b,11,12,12a-tetradecahydro-4H-imidazo[1,2-a]indeno[5,4-f]quinoline-8-carboxamide466.2596 3-6

N-(2,6-dichlorobenzyl)-(5aR,5bS, 7aS,8R, 10aS,10bS)-5,5a,5b6,7,7a,8,9,10,10a,10b,11,12,12a-tetradecahydro-4H-imidazo[1,2-a]indeno[5,4-f]quinoline-8-carboxamide500.2232 3-7

N-(2-fluorobenzyl)-(5aR,5bS, 7aS, 8R,10aS,10bS)-5,5a,5b6,7,7a,8,9,10,10a,10b,11,12,12a-tetradecahydro-4H-imidazo[1,2-a]indeno[5,4-f]quinoline-8-carboxamide450.2915 3-8

N-(3-fluorobenzyl)-(5aR,5bS, 7aS, 8R,10aS,10bS)-5,5a,5b6,7,7a,8,9,10,10a,10b,11,12,12a-tetradecahydro-4H-imidazo[1,2-a]indeno[5,4-f]quinoline-8-carboxamide450.2919 3-9

N-(2,6-difluorobenzyl)-(5aR,5bS, 7aS,8R, 10aS,10bS)-5,5a,5b6,7,7a,8,9,10,10a,10b,11,12,12a-tetradecahydro-4H-imidazo[1,2-a]indeno[5,4-f]quinoline-8-carboxamide468.282 3-10

N-(pyridin-2-ylmethyl)-(5aR,5bS, 7aS,8R, 10aS,10bS)-5,5a,5b6,7,7a,8,9,10,10a,10b,11,12,12a-tetradecahydro-4H-imidazo[1,2-a]indeno[5,4-f]quinoline-8-carboxamide433.2962 3-11

N-(2-methylbenzyl)-(5aR,5bS, 7aS, 8R,10aS,10bS)-5,5a,5b6,7,7a,8,9,10,10a,10b,11,12,12a-tetradecahydro-4H-imidazo[1,2-a]indeno[5,4-f]quinoline-8-carboxamide446.3177 3-12

N-(3-methylbenzyl)-(5aR,5bS, 7aS, 8R,10aS,10bS)-5,5a,5b6,7,7a,8,9,10,10a,10b,11,12,12a-tetradecahydro-4H-imidazo[1,2-a]indeno[5,4-f]quinoline-8-carboxamide446.3177 3-13

N-(4-methylbenzyl)-(5aR,5bS, 7aS, 8R,10aS,10bS)-5,5a,5b6,7,7a,8,9,10,10a,10b,11,12,12a-tetradecahydro-4H-imidazo[1,2-a]indeno[5,4-f]quinoline-8-carboxamide446.3177 3-14

N-[(1R)-1-phenylethyl)]-(5aR,5bS, 7aS,8R, 10aS,10bS)-5,5a,5b6,7,7a,8,9,10,10a,10b,11,12,12a-tetradecahydro-4H-imidazo[1,2-a]indeno[5,4-f]quinoline-8-carboxamide460.3338 3-15

N-(1H-benzimidazol-2-ylmethyl)-(5aR,5bS, 7aS, 8R, 10aS,10bS)-5,5a,5b6,7,7a,8,9,10,10a,10b,11,12,12a-tetradecahydro-4H-imidazo[1,2-a]indeno[5,4-f]quinoline-8-carboxamide472.3072 3-16

N-(1H-imidazo[4,5-b]pyridin-2-ylmethyl)-(5aR,5bS, 7aS, 8R,10aS,10bS)-5,5a,5b6,7,7a,8,9,10,10a,10b,11,12,12a-tetradecahydro-4H-imidazo[1,2-a]indeno[5,4-f]quinoline-8-carboxamide473.3031 3-17

N-[(4-phenyl-1H-imidazol-2-yl)methyl]-(5aR,5bS, 7aS, 8R, 10aS,10bS)-5,5a,5b6,7,7a,8,9,10,10a,10b,11,12,12a-tetradecahydro-4H-imidazo[1,2-a]indeno[5,4-f]quinoline-8-carboxamide498.324 3-18

N-[(5-chloro-1H-benzoimidazol-2-yl)methyl]-(5aR,5bS, 7aS, 8R,10aS,10bS)-5,5a,5b6,7,7a,8,9,10,10a,10b,11,12,12a-tetradecahydro-4H-imidazo[1,2-a]indeno[5,4-f]quinoline-8-carboxamide506.2697 3-19

N--[(5-methoxy-1H-benzoimidazol-2-yl)methyl]-(5aR,5bS, 7aS, 8R,10aS,10bS)-5,5a,5b6,7,7a,8,9,10,10a,10b,11,12,12a-tetradecahydro-4H-imidazo[1,2-a]indeno[5,4-f]quinoline-8-carboxamide470.2915

EXAMPLE 4

Pharmaceutical Composition

As a specific embodiment of this invention, 100 mg of,N-(2,6-dichlorobenzyl)-(5aR,5bS, 7aS, 8R, 10aS,10bS)-5,5a,5b6,7,7a,8,9,10,10a,10b,11,12,12a-tetradecahydro4H-imidazo[1,2-a]indeno[5,4-f]quinoline-8-carboxamideis formulated with sufficient finely divided lactose to provide a totalamount of 580 to 590 mg to fill a size 0, hard gelatin capsule.

While the foregoing specification teaches the principles of the presentinvention, with examples provided for the purpose of illustration, it isunderstood that the practice of the invention encompasses all of theusual variations, adoptions, or modifications, as being within the scopeof the following claims and their equivalents.

ASSAYS

In Vitro and In Vivo Assays for SARM Activity Identification ofCompounds

The compounds exemplified in the present application exhibited activityin one or more of the following assays.

Hydroxylapatite-Based Radioligand Displacement Assay of CompoundAffinity for Endogenously Expressed AR

Materials:

-   Binding Buffer: TEGM (10 mM Tris-HCl, 1 mM EDTA, 10% glycerol, 1 mM    beta-mecaptoethanol, 10 mM Sodium Molybdate, pH 7.2)-   50% HAP Slurry: Calbiochem Hydroxylapatite, Fast Flow, in 10 mM    Tris, pH 8.0 and 1 mM EDTA.-   Wash Buffer: 40 mM Tris, pH7.5, 100 mM KCl, 1 mM EDTA and 1 mM EGTA.-   95% EtOH-   Methyltrienolone, [17α-methyl-³H], (R1881*); NEN NET590-   Methyltrienolone (R1881), NEN NLP005 (dissolve in 95% EtOH)-   Dihydrotestosterone (DHT) [1,2,4,5,6,7-³H(N)] NEN NET453-   Hydroxylapatite Fast Flow; Calbiochem Cat#391947-   Molybdate=Molybdic Acid (Sigma, M1651)    MDA-MB-453 Cell Culture Media:

RPMI 1640 (Gibco 11835-055) w/23.8 mM NaHCO₃, 2 mM L-glutamine in 500 mLof complete media Final conc. 10 mL (1M Hepes) 20 mM 5 mL (200 mM L-glu)4 mM 0.5 mL (10 mg/mL human insulin) in 0.01N HCl 10 μg/mLCalbiochem#407694-S) 50 mL FBS (Sigma F2442) 10% 1 mL (10 mg/mLGentamicin Gibco#15710-072) 20 μg/mLCell Passaging

Cells (Hall R. E., et al., European Journal of Cancer, 30A: 484-490(1994)) are rinsed twice in PBS, phenol red-free Trypsin-EDTA is dilutedin the same PBS 1:10. The cell layers are rinsed with 1× Trypsin, extraTrypsin is poured out, and the cell layers are incubated at 37° C. for˜2 min. The flask is tapped and checked for signs of cell detachment.Once the cells begin to slide off the flask, the complete media is addedto kill the trypsin. The cells are counted at this point, then dilutedto the appropriate concentration and split into flasks or dishes forfurther culturing (Usually 1:3 to 1:6 dilution).

Preparation of MDA-MB-453 Cell Lysate

When the MDA cells are 70 to 85% confluent, they are detached asdescribed above, and collected by centrifuging at 1000 g for 10 minutesat 4° C. The cell pellet is washed twice with TEGM (10 mM Tris-HCl, 1 mMEDTA, 10% glycerol, 1 mM beta-mercaptoethanol, 10 mM Sodium Molybdate,pH 7.2). After the final wash, the cells are resuspended in TEGM at aconcentration of 10⁷ cells/mL. The cell suspension is snap frozen inliquid nitrogen or ethanol/dry ice bath and transferred to −80° C.freezer on dry ice. Before setting up the binding assay, the frozensamples are left on ice-water to just thaw (˜1 hr). Then the samples arecentrifuged at 12,500 g to 20,000 g for 30 min at 4° C. The supernatantis used to set-up assay right away. If using 50 μL of supernatant, thetest compound can be prepared in 50 μL of the TEGM buffer.

Procedure for Multiple Compound Screening

1× TEGM buffer is prepared, and the isotope-containing assay mixture isprepared in the following order: EtOH (2% final concentration inreaction), ³H-R1881 or ³H-DHT (0.5 nM final Conc. in reaction) and 1×TEGM. [e.g. For 100 samples, 200 μL (100×2) of EtOH+4.25 μL of 1:10³H-R1881 stock+2300 μL (100×23) 1× TEGM]. The compound is seriallydiluted, e.g., if starting final conc. is 1 μM, and the compound is in25 μL of solution, for duplicate samples, 75 μL of 4×1 μM solution ismade and 3 μL of 100 μM is added to 72 μL of buffer, and 1:5 serialdilution.

25μL of ³H-R1881 trace and 25 μL compound solution are first mixedtogether, followed by addition of 50 μL receptor solution. The reactionis gently mixed, spun briefly at about 200 rpm and incubated at 4° C.overnight. 100 μL of 50% HAP slurry is prepared and added to theincubated reaction which is then vortexed and incubated on ice for 5 to10 minutes. The reaction mixture is vortexed twice more to resuspend HAPwhile incubating reaction. The samples in 96-well format are then washedin wash buffer using The FilterMate™ Universal Harvester plate washer(Packard). The washing process transfers HAP pellet containingligand-bound expressed receptor to Unifilter-96 GF/B filter plate(Packard). The HAP pellet on the filter plate is incubated with 50 μL ofMICROSCINT (Packard) scintillint for 30 minutes before being counted onthe TopCount microscintillation counter (Packard). IC₅₀s are calculatedusing R1881 as a reference.

The compounds, Examples 1-1 through 1-19, and Examples 2-1 through 2-15,found in Tables 1 and 2, were tested in the above assay and found tohave an IC₅₀ value of 1 micromolar or less.

Mammalian Two-Hybrid Assay for the Ligand-Induced Interaction ofN-Terminus and C-Terminus Domains of the Androgen Receptor (AgonistMode: VIRCON)

This assay assesses the ability of AR agonists to induce the interactionbetween the N-terminal domain (NTD) and C-terminal domain (CTD) of rhARthat reflects the in vivo virilizing potential mediated by activatedandrogen receptors. The interaction of NTD and CTD of rhAR is quantifiedas ligand induced association between a Gal4DBD-rhARCTD fusion proteinand a VP16-rhARNTD fusion protein as a mammalian two-hybrid assay inCV-1 monkey kidney cells.

The day before transfection, CV-1 cells are trypsinized and counted, andthen plated at 20,000 cells/well in 96-well plates or larger plates(scaled up accordingly) in DMEM+10% FCS. The next morning, CV-1 cellsare cotransfected with pCBB1 (Gal4DBD-rhARLBD fusion construct expressedunder the SV40 early promoter), pCBB2 (VP16-rhAR NTD fusion constructexpressed under the SV40 early promoter) and pFR (Gal4 responsiveluciferase reporter, Promega) using LIPOFECTAMINE PLUS reagent(GIBCO-BRL) following the procedure recommended by the vendor. Briefly,DNA admixture of 0.05 μg pCBB 1, 0.05 μg pCBB2 and 0.1 μg of pFR ismixed in 3.4 μL OPTI-MEM (GIBCO-BRL) mixed with “PLUS Reagent” (1.6 μL,GIBCO-BRL) and incubated at room temperature (RT) for 15 min to form thepre-complexed DNA.

For each well, 0.4 μL LIPOFECTAMINE Reagent (GEBCO-BRL) is diluted into4.6 μL OPTI-MEM in a second tube and mixed to form the dilutedLIPOFECTAMINE Reagent. The pre-complexed DNA (above) and the dilutedLIPOFECTAMINE Reagent (above) are combined, mixed and incubated for 15minutes at room temperature. The medium on the cells is replaced with 40μL/well OPTI-MEM, and 10 μL DNA-lipid complexes are added to each well.The complexes are mixed into the medium gently and incubated at 37° C.at 5% CO₂ for 5 hours. Following incubation, 200 μL /well D-MEM and 13%charcoal-stripped FCS are added, followed by incubation at 37° C. at 5%CO₂. After 24 hours, the test compounds are added at the desiredconcentration(s) (1 nM-10 μM). Forty eight hours later, luciferaseactivity is measured using LUC-Screen system (TROPIX) following themanufacturer's protocol. The assay is conducted directly in the wells bysequential addition of 50 μL each of assay solution 1 followed by assaysolution 2. After incubation for 40 minutes at room temperature,luminescence is directly measured with 2-5 second integration.

Activity of test compounds is calculated as the E_(max) relative to theactivity obtained with 3nM R1881. Typical tissue-selective androgenreceptor modulators of the present invention display weak or no agonistactivity in this assay with less than 50% agonist activity at 10micromolar.

See He B, Kemppainen J A, Voegel J J, Gronemeyer H, Wilson E M,“Activation function in the human androgen receptor ligand bindingdomain mediates inter-domain communication with the NH(2)-terminaldomain,” J. Biol. Chem. 274: 37219-37225 (1999).

Trans-Activation Modulation of Androgen Receptor (TAMAR)

This assay assesses the ability of test compounds to controltranscription from the MMTV-LUC reporter gene in MDA-MB-453 cells, ahuman breast cancer cell line that naturally expresses the human AR. Theassay measures induction of a modified MMTV LTR/promoter linked to theLUC reporter gene.

20,000 to 30,000 cells/well are plated in a white, clear bottom 96-wellplate in “Exponential Growth Medium” which consists of phenol red-freeRPMI 1640 containing 10%FBS, 4 mM L-glutamine, 20 mM HEPES, 10 ug/mLhuman insulin, and 20 ug/mL gentamicin. Incubator conditions are 37° C.and 5% CO₂. The transfectin is done in batch mode. The cells aretrypsinized and counted to the right cell number in the proper amount offresh media, and then gently mixed with the Fugene/DNA cocktail mix andplated onto the 96-well plate. All the wells receive 200 Tl ofmedium+lipid/DNA complex and are then incubated at 37° C. overnight. Thetransfection cocktail consists of serum-free Optimem, Fugene6 reagentand DNA. The manufacturer's (Roche Biochemical) protocol for cocktailsetup is followed. The lipid (Tl) to DNA (Tg) ratio is approximately 3:2and the incubation time is 20 minutes at room temperature. Sixteen to 24hrs after transfection, the cells are treated with test compounds suchthat the final DMSO (vehicle) concentration is <3%. The cells areexposed to the test compounds for 48 hours. After 48 hours, the cellsare lysed by a Promega cell culture lysis buffer for 30-60 minutes andthen the luciferase activity in the extracts is assayed in the 96-wellformat luminometer.

Activity of test compounds is calculated as the E_(max) relative to theactivity obtained with 100 nM R1881.

See R. E. Hall, et al., “MDA-MB-453, an androgen-responsive human breastcarcinoma cell line with high androgen receptor expression,” Eur. J.Cancer, 30A: 484-490 (1994) and R. E. Hall, et al., “Regulation ofandrogen receptor gene expression by steroids and retinoic acid in humanbreast-cancer cells,” Int. J. Cancer., 52: 778-784 (1992).

Activity of test compounds is calculated as the E_(max) relative to theactivity obtained with R1881. The exemplified tissue selective androgenreceptor modulators of the present invention display partial agonistactivity in this assay of greater than 10%.

In Vivo Prostate Assay

Male Sprague-Dawley rats aged 9-10 weeks, the earliest age of sexualmaturity, are used in prevention mode. The goal is to measure the degreeto which androgen-like compounds delay the rapid deterioration (˜−85%)of the ventral prostate gland and seminal vesicles that occurs during aseven day period after removal of the testes (orchiectomy [ORX]).

Rats are orchiectomized (ORX). Each rat is weighed, then anesthetized byisoflurane gas that is maintained to effect. A 1.5 cm anteroposteriorincision is made in the scrotum. The right testicle is exteriorized. Thespermatic artery and vas deferens are ligated with 4.0 silk 0.5 cmproximal to the testicle. The testicle is freed by one cut of a smallsurgical scissors distal to the ligation site. The tissue stump isreturned to the scrotum. The same is repeated for the left testicle.When both stumps are returned to the scrotum, the scrotum and overlyingskin are sutured closed with 4.0 silk. For Sham-ORX, all proceduresexcepting ligation and scissors cutting are completed. The rats fullyrecover consciousness and full mobility within 10-15 minutes.

A dose of test compound is administered subcutaneously or orally to therat immediately after the surgical incision is sutured. Treatmentcontinues for an additional six consecutive days.

Necropsy and Endpoints

The rat is first weighed, then anesthetized in a CO₂ chamber until neardeath. Approximately 5 ml whole blood is obtained by cardiac puncture.The rat is then examined for certain signs of death and completeness ofORX. Next, the ventral portion of the prostate gland is located andblunt dissected free in a highly stylized fashion. The ventral prostateis blotted dry for 3-5 seconds and then weighed (VPW). Finally, theseminal vesicle is located and dissected free. The ventral seminalvesicle is blotted dry for 3-5 seconds and then weighed (SVWT).

Primary data for this assay are the weights of the ventral prostate andseminal vesicle. Secondary data include serum LH (luteinizing hormone)and FSH (follicle stimulating hormone), and possible serum markers ofbone formation and virilization. Data are analyzed by ANOVA plus FisherPLSD post-hoc test to identify intergroup differences. The extent towhich test compounds inhibit ORX-induced loss of VPW and SVWT isassessed.

In Vivo Bone Formation Assay

Female Sprague-Dawley rats aged 7-10 months are used in treatment modeto simulate adult human females. The rats have been ovariectomized (OVX)75-180 days previously, to cause bone loss and simulate estrogendeficient, osteopenic adult human females. Pre-treatment with a low doseof a powerful anti-resorptive, alendronate (0.0028mpk SC, 2×/wk) isbegun on Day 0. On Day 15, treatment with test compound is started. Testcompound treatment occurs on Days 15-31 with necropsy on Day 32. Thegoal is to measure the extent to which androgen-like compounds increasethe amount of bone formation, shown by increased fluorochrome labeling,at the periosteal surface.

In a typical assay, nine groups of seven rats each are studied.

On Days 19 and 29 (fifth and fifteenth days of treatment), a singlesubcutaneous injection of calcein (8mg/kg) is given to each rat.

Necropsy and Endpoints

The rat is first weighed, then anesthetized in a CO₂ chamber until neardeath. Approximately 5mL whole blood is obtained by cardiac puncture.The rat is then examined for certain signs of death and completeness ofOVX. First, the uterus is located, blunt dissected free in a highlystylized fashion, blotted dry for 3-5 seconds and then weighed (UW). Theuterus is placed in 10% neutral-buffered formalin. Next, the right legis disarticulated at the hip. The femur and tibia are separated at theknee, substantially defleshed, and then placed in 70% ethanol.

A 1-cm segment of the central right femur, with the femoralproximal-distal midpoint ats center, is placed in a scintillation vialand dehydrated and defatted in graded alcohols and acetone, thenintroduced to solutions with increasing concentrations of methylmethacrylate. It is embedded in a mixture of 90% methyl methacrylate:10% dibutyl phthalate that is allowed to polymerize over a 48-72 hoursperiod. The bottle is cracked and the plastic block is trimmed into ashape that conveniently fits the vice-like specimen holder of a Leica1600 Saw Microtome, with the long axis of the bone prepared forcross-sectioning. Three cross-sections of 85 μm thickness are preparedand mounted on glass slides. One section from each rat that approximatesthe midpoint of the bone is selected and blind-coded. The periostealsurface of each section is assessed for total periosteal surface, singlefluorochrome label, double fluorochrome label, and interlabel distance.

Primary data for this assay are the percentage of periosteal surfacebearing double label and the mineral apposition rate (interlabeldistance(μm)/10d), semi-independent markers of bone formation. Secondarydata include uterus weight and histologic features. Tertiary endpointscan include serum markers of bone formation and virilization. Data areanalyzed by ANOVA plus Fisher PLSD post-hoc test to identify intergroupdifferences. The extent to which test compounds increase bone formationendpoint are assessed.

1. A compound of structural formula I:

or an enantiomer or a pharmaceutically acceptable salt thereof; whereina-b represents CH═CH or CH₂CH₂; d is 0 or 1; R¹ is selected fromhydrogen, C₁₋₄ alkyl, wherein said C₁₋₄ alkyl is optionally substitutedwith one or more substituents independently selected from halogen,hydroxy, C₁₋₄ alkoxy, and C₁₋₄ alkylamino, and R² is chosen fromhydrogen, hydroxy C₀₋₁₀alkyl, perfluoroC₁₋₆alkyl, perfluoroC₁₋₆alkoxy,C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, aryl C₀₋₁₀ alkyl, C₃₋₈cycloalkyl C₀₋₁₀ alkyl, C₃₋₈ heterocyclyl C₀₋₁₀ alkyl, (C₀₋₁₀alkyl)₁₋₂aminocarbonyloxy C₀₋₁₀ alkyl, (aryl C₀₋₁₀alkyl)₁₋₂aminocarbonyloxy C₀₋₁₀ alkyl, (C₃₋₈ cycloalkyl C₀₋₁₀alkyl)₁₋₂aminocarbonyloxy C₀₋₁₀ alkyl, (C₃₋₈ heterocyclyl C₀₋₁₀alkyl)₁₋₂aminocarbonyloxy C₀₋₁₀ alkyl, (C₀₋₁₀alkyl)₁₋₂aminocarbonylaminoC₁₋₁₀ alkyl, (aryl C₀₋₁₀alkyl)₁₋₂aminocarbonylamino C₁₋₁₀ alkyl, (C₃₋₈ cycloalkyl C₀₋₁₀alkyl)₁₋₂aminocarbonylamino C₁₋₁₀ alkyl, (C₃₋₈ heterocyclyl C₀₋₁₀alkyl)₁₋₂aminocarbonylamino C₁₋₁₀ alkyl, (C₀₋₁₀ alkyl)₁₋₂aminocarbonylC₀₋₁₀ alkyl, (aryl C₀₋₁₀ alkyl)₁₋₂aminocarbonyl C₀₋₁₀ alkyl, C₃₋₈cycloalkyl C₀₋₁₀ alkyl aminocarbonyl C₀₋₁₀ alkyl, C₃₋₈ heterocyclylC₀₋₁₀ alkyl aminocarbonyl C₀₋₁₀ alkyl, C₀₋₁₀ alkyl carbonylamino C₁₋₁₀alkyl, C₃₋₈ cycloalkyl C₀₋₁₀ alkyl carbonylamino C₁₋₁₀ alkyl, C₃₋₈heterocyclyl C₀₋₁₀ alkyl carbonylamino C₁₋₁₀ alkyl, aryl C₀₋₁₀ alkylcarbonylamino C₁₋₁₀ alkyl, C₀₋₁₀ alkyloxy carbonylamino C₁₋₁₀ alkyl,C₃₋₈ cycloalkyl C₀₋₁₀ alkyloxy carbonylamino C₁₋₁₀ alkyl, C₃₋₈heterocyclyl C₀₋₁₀ alkyloxy carbonylamino C₁₋₁₀ alkyl, aryl C₀₋₁₀alkyloxy carbonylamino C₁₋₁₀ alkyl, C₀₋₁₀ alkyloxy carbonyloxy C₀₋₁₀alkyl, C₃₋₈ cycloalkyl C₀₋₁₀ alkyloxy carbonyloxy C₀₋₁₀ alkyl, C₃₋₈heterocyclyl C₀₋₁₀ alkyloxy carbonyloxy C₀₋₁₀ alkyl, aryl C₀₋₁₀ alkyloxycarbonyloxy C₀₋₁₀ alkyl, C₁₋₁₀ alkoxy (carbonyl)₀₋₁C₀₋₁₀ alkyl,C₁₋₁₀alkyloxy C₀₋₁₀alkyl, aryloxy C₀₋₁₀ alkyl, C₃₋₈ cycloalkyloxy C₀₋₁₀alkyl, C₃₋₈ heterocyclyloxy C₀₋₁₀ alkyl, C₃₋₈ heterocyclylC₀₋₁₀alkyloxyC₀₋₁₀ alkyl, and C₁₋₁₀ alkylcarbonyloxy C₀₋₁₀ alkyl; wherein in R², saidaryl is selected from phenyl, naphthyl, indanyl, and tetrahydronapthyl,and said heterocyclyl is selected from azabenzimidazolyl,benzimidazolyl, benzofuranyl, benzothiophenyl, benzoxazolyl,benzothiazolyl, benzodihydrofuranyl, 1,3-benzodioxolyl,2,3-dihydro-1,4-benzodioxinyl, imidazolyl, indanyl, indolyl, indazoyl,isoquinolyl, isothiazolyl, isoxazolyl, quinolyl, furanyl, thienyl,oxazolyl, thiazolyl, pyrazolyl, pyrrolyl, pyridyl, pyrimidyl, pyrazinyl,thiadiazolyl, oxadiazolyl, triazolyl, imidizopyridinyl, and tetrazolyl;and further wherein in R² is optionally substituted with one or moregroups, R³, chosen from halogen, aryl, C₁₋₈ alkyl, C₃₋₈ cycloalkyl, C₃₋₈cycloheteroalkyl, aryl-C₁₋₆ alkyl, amino-C₀₋₆ alkyl, C₁₋₆alkylamino-C₀₋₆ alkyl, (C₁₋₆ alkyl)₂amino-C₀₋₆ alkyl, aryl-C₀₋₆alkylamino-C₀₋₆ alkyl, (aryl-C₀₋₆ alkyl)₂amino-C₀₋₆ alkyl, C₁₋₆alkylthio, aryl-C₀₋₆ alkylthio, C₁₋₆ alkylsulfinyl, aryl-C₀₋₆alkylsulfinyl, C₁₋₆ alkylsulfonyl, aryl-C₀₋₆ alkylsulfonyl, C₁₋₆alkoxy-C₀₋₆ alkyl, aryl-C₀₋₆ alkoxy-C₀₋₆ alkyl, hydroxycarbonyl-C₀₋₆alkyl, C₁₋₆ alkoxycarbonyl-C₀₋₆ alkyl, aryl-C₀₋₆ alkoxycarbonyl-C₀₋₆alkyl, hydroxycarbonyl-C₁₋₆ alkyloxy, hydroxy-C₀₋₆ alkyl, cyano, nitro,perfluoro-C₁₋₄ alkyl, perfluoro-C₁₋₄ alkoxy, C₁₋₆ alkylcarbonyloxy,aryl-C₀₋₆ alkylcarbonyloxy, C₁₋₆alkylcarbonylamino, aryl-C₀₋₆alkylcarbonylamino, C₁₋₆ alkylsulfonylamino, aryl-C₀₋₆alkylsulfonylamino, C₁₋₆ alkoxycarbonylamino, aryl-C₀₋₆alkoxycarbonylamino, C₁₋₆ alkylaminocarbonylamino, aryl-C₀₋₆alkylamino-carbonylamino, (C₁₋₆ alkyl)₂ aminocarbonylamino, (aryl-C₀₋₆alkyl)₂ aminocarbonylamino, (C₁₋₆ alkyl)₂ aminocarbonyloxy, and(aryl-C₀₋₆ alkyl)₂ aminocarbonyloxy; and wherein R³ is optionallysubstituted with one or more groups chosen from: OH, C₁₋₆ alkoxy,halogen, CO₂H, CN, O(C═O) C₁₋₆ alkyl, NO₂, trifluoromethoxy,trifluoroethoxy, —O(_(d))(C₁₋₁₀)perfluoroalkyl, and NH₂.
 2. A compoundof claim 1, chosen from: N-(2,6-dichloropyridin-3-yl)-(5aR,5bS, 7aS, 8R,10aS,10bS)-5b,6,7,7a,8,9,10,10a,10b,11,12,12a-dodecahydro-5aH-imidazo[1,2-a]indeno[5,4-f]quinoline-8-carboxamide;N-(2-cyano-3-fluorophenyl)-(5aR,5bS, 7aS, 8R, 10aS,10bS)-5b,6,7,7a,8,9,10,10a,10b,11,12,12a-dodecahydro-5aH-imidazo[1,2-a]indeno[5,4-f]quinoline-8-carboxamide;N-(2-cyano-3-chlorophenyl)-(5aR,5bS, 7aS, 8R, 10aS,10bS)-5b,6,7,7a,8,9,10,10a,10b,11,12,12a-dodecahydro-5aH-imidazo[1,2-a]indeno[5,4-f]quinoline-8-carboxamide;N-(2-cyano-4-chlorophenyl)-(5aR,5bS, 7aS, 8R, 10aS,10bS)-5b,6,7,7a,8,9,10,10a,10b,11,12,12a-dodecahydro-5aH-imidazo[1,2-a]indeno[5,4-f]quinoline-8-carboxamide;N-(2-cyano-3-methylphenyl)-(5aR,5bS, 7aS, 8R, 10aS,10bS)-5b,6,7,7a,8,9,10,10a,10b,11,12,12a-dodecahydro-5aH-imidazo[1,2-a]indeno[5,4-f]quinoline-8-carboxamide;N-(2-chlorophenyl)-(5aR,5bS, 7aS, 8R, 10aS,10bS)-5b,6,7,7a,8,9,10,10a,10b,11,12,12a-dodecahydro-5aH-imidazo[1,2-a]indeno[5,4-f]quinoline-8-carboxamide;N-(2-cyano-5-methylphenyl)-(5aR,5bS, 7aS, 8R, 10aS,10bS)-5b,6,7,7a,8,9,10,10a,10b,11,12,12a-dodecahydro-5aH-imidazo[1,2-a]indeno[5,4-f]quinoline-8-carboxamide;N-(3-chlorophenyl)-(5aR,5bS, 7aS, 8R, 10aS,10bS)-5b,6,7,7a,8,9,10,10a,10b,11,12,12a-dodecahydro-5aH-imidazo[1,2-a]indeno[5,4-f]quinoline-8-carboxamide;N-(2,6-dichlorophenyl)-(5aR,5bS, 7aS, 8R, 10aS,10bS)-5b,6,7,7a,8,9,10,10a,10b,11,12,12a-dodecahydro-5aH-imidazo[1,2-a]indeno[5,4-f]quinoline-8-carboxamide;N-(2-fluorophenyl)-(5aR,5bS, 7aS, 8R, 10aS, 10bS)-5b,6,7,7a,8,9,10,10a,10b,11,12,12a-dodecahydro-5aH-imidazo[1,2-a]indeno[5,4-f]quinoline-8-carboxamide;N-(3-fluorophenyl)-(5aR,5bS, 7aS, 8R, 10aS,10bS)-5b,6,7,7a,8,9,10,10a,10b,11,12,12a-dodecahydro-5aH-imidazo[1,2-a]indeno[5,4-f]quinoline-8-carboxamide;N-Benzyl-(5aR,5bS, 7aS, 8R, 10aS, 10bS)-5b,6,7,7a,8,9,10,10a,10b,11,12,12a-dodecahydro-5aH-imidazo[1,2-a]indeno[5,4-f]quinoline-8-carboxamide;N-(1-phenylethyl)-(5aR,5bS, 7aS, 8R, 10aS,10bS)-5b,6,7,7a,8,9,10,10a,10b,11,12,12a-dodecahydro-5aH-imidazo[1,2-a]indeno[5,4-f]quinoline-8-carboxamide;N-[(1-(2-chlorophenyl)ethyl]-(5aR,5bS, 7aS, 8R, 10aS,10bS)-5b,6,7,7a,8,9,10,10a,10b,11,12,12a-dodecahydro-5aH-imidazo[1,2-a]indeno[5,4-f]quinoline-8-carboxamide;N-[(1-(3-chlorophenyl)ethyl]-(5aR,5bS, 7aS, 8R, 10aS,10bS)-5b,6,7,7a,8,9,10,10a,10b,11,12,12a-dodecahydro-5aH-imidazo[1,2-a]indeno[5,4-f]quinoline-8-carboxamide;N-[(1-(2,6-dichlorophenyl)ethyl]-(5aR,5bS, 7aS, 8R, 10aS, 10bS)-5b,6,7,7a,8,9,10,10a,10b,11,12,12a-dodecahydro-5aH-imidazo[1,2-a]indeno[5,4-f]quinoline-8-carboxamide;N-[1-(1,3-benzodioxol-5-yl)ethyl]-(5aR,5bS, 7aS, 8R, 10aS, 10bS)-5b,6,7,7a,8,9,10,10a,10b,11,12,12a-dodecahydro-5aH-imidazo[1,2-a]indeno[5,4-f]quinoline-8-carboxamide;N-[(1H-imidazol-2-yl)methyl]-(5aR,5bS, 7aS, 8R, 10aS,10bS)-5b,6,7,7a,8,9,10,10a,10b,11,12,12a-dodecahydro-5aH-imidazo[1,2-a]indeno[5,4-f]quinoline-8-carboxamide;N-[(4-methyl-1H-imidazol-2-yl)methyl]-((5aR,5bS, 7aS, 8R, 10aS,10bS)-5b,6,7,7a,8,9,10,10a,10b,11,12,12a-dodecahydro-5aH-imidazo[1,2-a]indeno[5,4-f]quinoline-8-carboxamide;N-(1H-benzimidazol-2-ylmethyl)-(5aR,5bS, 7aS, 8R, 10aS, 10bS)-5b,6,7,7a,8,9,10,10a,10b,11,12,12a-dodecahydro-5aH-imidazo[1,2-a]indeno[5,4-f]quinoline-8-carboxamide;N-(5-methoxy-1H-benzimidazol-2-ylmethyl)-((5aR,5bS, 7aS, 8R, 10aS,10bS)-5b,6,7,7a,8,9,10,10a,10b,11,12,12a-dodecahydro-5aH-imidazo[1,2-a]indeno[5,4-f]quinoline-8-carboxamide;N-(2-fluorobenzyl)-(5aR,5bS, 7aS, 8R, 10aS,10bS)-5b,6,7,7a,8,9,10,10a,10b,11,12,12a-dodecahydro-5aH-imidazo[1,2-a]indeno[5,4-f]quinoline-8-carboxamide;N-(3-fluorobenzyl)-(5aR,5bS, 7aS, 8R, 10aS,10bS)-5b,6,7,7a,8,9,10,10a,10b,11,12,12a-dodecahydro-5aH-imidazo[1,2-a]indeno[5,4-f]quinoline-8-carboxamide;N-(4-fluorobenzyl)-(5aR,5bS, 7aS, 8R, 10aS, 10bS)-5b,6,7,7a,8,9,10,10a,10b,11,12,12a-dodecahydro-5aH-imidazo[1,2-a]indeno[5,4-f]quinoline-8-carboxamide;N-(2,6-difluorobenzyl)-(5aR,5bS, 7aS, 8R, 10aS,10bS)-5b,6,7,7a,8,9,10,10a,10b,11,12,12a-dodecahydro-5aH-imidazo[1,2-a]indeno[5,4-f]quinoline-8-carboxamide;N-(pyridin-2-ylmethyl)-(5aR,5bS, 7aS, 8R, 10aS,10bS)-5b,6,7,7a,8,9,10,10a,10b,11,12,12a-dodecahydro-5aH-imidazo[1,2-a]indeno[5,4-f]quinoline-8-carboxamide;N-(pyridin-3-ylmethyl)-(5aR,5bS, 7aS, 8R, 10aS,10bS)-5b,6,7,7a,8,9,10,10a,10b,11,12,12a-dodecahydro-5aH-imidazo[1,2-a]indeno[5,4-f]quinoline-8-carboxamide;N-(pyridin-4-ylmethyl)-(5aR,5bS, 7aS, 8R, 10aS,10bS)-5b,6,7,7a,8,9,10,10a,10b,11,12,12a-dodecahydro-5aH-imidazo[1,2-a]indeno[5,4-f]quinoline-8-carboxamide;N-(2-methylbenzyl)-(5aR,5bS, 7aS, 8R, 10aS,10bS)-5b,6,7,7a,8,9,10,10a,10b,11,12,12a-dodecahydro-5aH-imidazo[1,2-a]indeno[5,4-f]quinoline-8-carboxamide;N-(3-methylbenzyl)-(5aR,5bS, 7aS, 8R, 10aS, 10bS)-5b,6,7,7a,8,9,10,10a,10b,11,12,12a-dodecahydro-5aH-imidazo[1,2-a]indeno[5,4-f]quinoline-8-carboxamide;N-(4-methylbenzyl)-(5aR,5bS, 7aS, 8R, 10aS,10bS)-5b,6,7,7a,8,9,10,10a,10b,11,12,12a-dodecahydro-5aH-imidazo[1,2-a]indeno[5,4-f]quinoline-8-carboxamide;N-(1R,1-phenylpropyl)-(5aR,5bS, 7aS, 8R, 10aS,10bS)-5b,6,7,7a,8,9,10,10a,10b,11,12,12a-dodecahydro-5aH-imidazo[1,2-a]indeno[5,4-f]quinoline-8-carboxamide;N-(1S, 1-phenylpropyl)-(5aR,5bS, 7aS, 8R, 10aS,10bS)-5b,6,7,7a,8,9,10,10a,10b,11,12,12a-dodecahydro-5aH-imidazo[1,2-a]indeno[5,4-f]quinoline-8-carboxamide;N-(1H-imidazo[4,5-b]pyridin-2-ylmethyl)-(5aR,5bS, 7aS, 8R, 10aS,10bS)-5b,6,7,7a,8,9,10,10a,10b,11,12,12a-dodecahydro-5aH-imidazo[1,2-a]indeno[5,4-f]quinoline-8-carboxamide;N-[(4-methylthio-1H-imidazol-2-yl)methyl]-(5aR,5bS, 7aS, 8R, 10aS,10bS)-5b,6,7,7a,8,9,10,10a,10b,11,12,12a-dodecahydro-5aH-imidazo[1,2-a]indeno[5,4-f]quinoline-8-carboxamide;N-(2-chloro-4-cyanophenyl)-(5aR,5bS, 7aS, 8R, 10aS,10bS)-5b,6,7,7a,8,9,10,10a,10b,11,12,12a-dodecahydro-5aH-imidazo[1,2-a]indeno[5,4-f]quinoline-8-carboxamide;N-(3,5-dichloropyridin-2-yl)-(5aR,5bS, 7aS, 8R, 10aS,10bS)-5b,6,7,7a,8,9,10,10a,10b,11,12,12a-dodecahydro-5aH-imidazo[1,2-a]indeno[5,4-f]quinoline-8-carboxamide;N-(4-chloropyridin-3-yl)-(5aR,5bS, 7aS, 8R, 10aS,10bS)-5b,6,7,7a,8,9,10,10a,10b,11,12,12a-dodecahydro-5aH-imidazo[1,2-a]indeno[5,4-f]quinoline-8-carboxamide;N-(2-chloropyridin-3-yl)-(5aR,5bS, 7aS, 8R, 10aS,10bS)-5b,6,7,7a,8,9,10,10a,10b,11,12,12a-dodecahydro-5aH-imidazo[1,2-a]indeno[5,4-f]quinoline-8-carboxamide;N-(2-chloropyridin-5-yl)-(5aR,5bS, 7aS, 8R, 10aS,10bS)-5b,6,7,7a,8,9,10,10a,10b,11,12,12a-dodecahydro-5aH-imidazo[1,2-a]indeno[5,4-f]quinoline-8-carboxamide;N-[1-(pyridin-2-yl)ethyl]-(5aR,5bS, 7aS, 8R, 10aS,10bS)-5b,6,7,7a,8,9,10,10a,10b,11,12,12a-dodecahydro-5aH-imidazo[1,2-a]indeno[5,4-f]quinoline-8-carboxamide;N-[1-(pyridin-3-yl)ethyl]-(5aR,5bS, 7aS, 8R, 10aS,10bS)-5b,6,7,7a,8,9,10,10a,10b,11,12,12a-dodecahydro-5aH-imidazo[1,2-a]indeno[5,4-f]quinoline-8-carboxamide;N-[1-(pyridin-4-yl)ethyl]-(5aR,5bS, 7aS, 8R, 10aS,10bS)-5b,6,7,7a,8,9,10,10a,10b,11,12,12a-dodecahydro-5aH-imidazo[1,2-a]indeno[5,4-f]quinoline-8-carboxamide;N-(primidin-4-yl)-(5aR,5bS, 7aS, 8R, 10aS, 10bS)-5b,6,7,7a,8,9,10,10a,10b,11,12,12a-dodecahydro-5aH-imidazo[1,2-a]indeno[5,4-f]quinoline-8-carboxamide;N-(5-cyanoprimidin-4-yl)-(5aR,5bS, 7aS, 8R, 10aS,10bS)-5b,6,7,7a,8,9,10,10a,10b,11,12,12a-dodecahydro-5aH-imidazo[1,2-a]indeno[5,4-f]quinoline-8-carboxamide;Methyl 2-{[(5aR,5bS, 7aS, 8R, 10aS,10bS)-5,5a,5b,6,7,7a,8,9,10,10a,10b,11,12,12a-tetradecahydro-4H-imidazo[1,2-α]indeno[5,4-f]quinolin-8-ylcarbonyl]amino}butanoate;N-[(1S)-1-(aminocarbonyl)propyl]-(5aR,5bS, 7aS, 8R, 10aS,10bS)-5b,6,7,7a,8,9,10,10a,10b,11,12,12a-dodecahydro-5aH-imidazo[1,2-a]indeno[5,4-f]quinoline-8-carboxamide;N-[(1S)-1-(methylaminocarbonyl)propyl](5aR,5bS, 7aS, 8R, 10aS,10bS)-5b,6,7,7a,8,9,10,10a,10b,11,12,12a-dodecahydro-5aH-imidazo[1,2-a]indeno[5,4-f]quinoline-8-carboxamide;N-[(1S)-1-(dimethylaminocarbonyl)propyl](5aR,5bS, 7aS, 8R, 10aS,10bS)-5b,6,7,7a,8,9,10,10a,10b,11,12,12a-dodecahydro-5aH-imidazo[1,2-a]indeno[5,4-f]quinoline-8-carboxamide;N-(2,2,2-trifluoroethyl)-(5aR,5bS, 7aS, 8R, 10aS, 10bS)-5b,6,7,7a,8,9,10,10a,10b,11,12,12a-dodecahydro-5aH-imidazo[1,2-a]indeno[5,4-f]quinoline-8-carboxamide;N-(3,3,3-trifluoropropyl)-(5aR,5bS, 7aS, 8R, 10aS,10bS)-5b,6,7,7a,8,9,10,10a,10b,11,12,12a-dodecahydro-5aH-imidazo[1,2-a]indeno[5,4-f]quinoline-8-carboxamide;N-[4-(cyanomethyl)phenyl]-(5aR,5bS, 7aS, 8R, 10aS,10bS)-5b,6,7,7a,8,9,10,10a,10b,11,12,12a-dodecahydro-5aH-imidazo[1,2-a]indeno[5,4-f]quinoline-8-carboxamide;Methyl 4-{[(5aR,5bS, 7aS, 8R, 10aS,10bS)-5b,6,7,7a,8,9,10,10a,10b,11,12,12a-dodecahydro-5aH-imidazo[1,2-α]indeno[5,4-f]quinolin-8-ylcarbonyl]amino}benzoate;N-[4-(aminocarbonyl)phenyl]-(5aR,5bS, 7aS, 8R, 10aS,10bS)-5b,6,7,7a,8,9,10,10a,10b,11,12,12a-dodecahydro-5aH-imidazo[1,2-α]indeno[5,4-f]quinoline-8-carboxamide;(5aR,5bS, 7aS, 8R, 10aS,10bS)-N-[4-(1,2,3-thiadiazol4-yl)phenyl]-5b,6,7,7a,8,9,10,10a,10b,11,12,12a-dodecahydro-5aH-imidazo[1,2-α]indeno[5,4-f]quinoline-8-carboxamide;(5aR,5bS, 7aS, 8R, 10aS, 10bS)-N-(1H-indazol-6-yl)-5b,6,7,7a,8,9,10,10a,10b,11,12,12a-dodecahydro-5aH-imidazo[1,2-α]indeno[5,4-f]quinoline-8-carboxamide;N-(2,6-dichlorophenyl)-(5aR,5bS, 7aS, 8R, 10aS,10bS)-5,5a,5b6,7,7a,8,9,10,10a,10b,11,12,12a-tetradecahydro-4H-imidazo[1,2-a]indeno[5,4-f]quinoline-8-carboxamide;N-(2-cyanophenyl)-(5aR,5bS, 7aS, 8R, 10aS,10bS)-5,5a,5b6,7,7a,8,9,10,10a,10b,11,12,12a-tetradecahydro-4H-imidazo[1,2-a]indeno[5,4-f]quinoline-8-carboxamide;N-(2-methyl-4-cyanophenyl)-(5aR,5bS, 7aS, 8R, 10aS,10bS)-5,5a,5b6,7,7a,8,9,10,10a,10b,11,12,12a-tetradecahydro4H-imidazo[1,2-a]indeno[5,4-f]quinoline-8-carboxamide;N-benzyl-(5aR,5bS, 7aS, 8R, 10aS,10bS)-5,5a,5b6,7,7a,8,9,10,10a,10b,11,12,12a-tetradecahydro-4H-imidazo[1,2-a]indeno[5,4-f]quinoline-8-carboxamide;N-(3-chlorobenzyl)-(5aR,5bS, 7aS, 8R, 10aS,10bS)-5,5a,5b6,7,7a,8,9,10,10a,10b,11,12,12a-tetradecahydro-4H-imidazo[1,2-a]indeno[5,4-f]quinoline-8-carboxamide;N-(2,6-dichlorobenzyl)-(5aR,5bS, 7aS, 8R, 10aS,10bS)-5,5a,5b6,7,7a,8,9,10,10a,10b,11,12,12a-tetradecahydro-4H-imidazo[1,2-a]indeno[5,4-f]quinoline-8-carboxamide;N-(2-fluorobenzyl)-(5aR,5bS, 7aS, 8R, 10aS,10bS)-5,5a,5b6,7,7a,8,9,10,10a,10b,11,12,12a-tetradecahydro-4H-imidazo[1,2-a]indeno[5,4-f]quinoline-8-carboxamide;N-(3-fluorobenzyl)-(5aR,5bS, 7aS, 8R, 10aS,10bS)-5,5a,5b6,7,7a,8,9,10,10a,10b,11,12,12a-tetradecahydro-4H-imidazo[1,2-a]indeno[5,4-f]quinoline-8-carboxamide;N-(2,6-difluorobenzyl)-(5aR,5bS, 7aS, 8R, 10aS,10bS)-5,5a,5b6,7,7a,8,9,10,10a,10b,11,12,12a-tetradecahydro-4H-imidazo[1,2-a]indeno[5,4-f]quinoline-8-carboxamide;N-(pyridin-2-ylmethyl)-(5aR,5bS, 7aS, 8R, 10aS,10bS)-5,5a,5b6,7,7a,8,9,10,10a,10b,11,12,12a-tetradecahydro-4H-imidazo[1,2-a]indeno[5,4-f]quinoline-8-carboxamide;N-(2-methylbenzyl)-(5aR,5bS, 7aS, 8R, 10aS,10bS)-5,5a,5b6,7,7a,8,9,10,10a,10b,11,12,12a-tetradecahydro-4H-imidazo[1,2-a]indeno[5,4-f]quinoline-8-carboxamide;N-(3-methylbenzyl)-(5aR,5bS, 7aS, 8R, 10aS,10bS)-5,5a,5b6,7,7a,8,9,10,10a,10b,11,12,12a-tetradecahydro-4H-imidazo[1,2-a]indeno[5,4-f]quinoline-8-carboxamide;N-(4-methylbenzyl)-(5aR,5bS, 7aS, 8R, 10aS,10bS)-5,5a,5b6,7,7a,8,9,10,10a,10b,11,12,12a-tetradecahydro4H-imidazo[1,2-a]indeno[5,4-f]quinoline-8-carboxamide;N-[(1R)-1-phenylethyl)]-(5aR,5bS, 7aS, 8R, 10aS,10bS)-5,5a,5b6,7,7a,8,9,10,10a,10b,11,12,12a-tetradecahydro-4H-imidazo[1,2-a]indeno[5,4-f]quinoline-8-carboxamide;N-(1H-benzimidazol-2-ylmethyl)-(5aR,5bS, 7aS, 8R, 10aS,10bS)-5,5a,5b6,7,7a,8,9,10,10a,10b,11,12,12a-tetradecahydro-4H-imidazo[1,2-a]indeno[5,4-f]quinoline-8-carboxamide;N-(1H-imidazo[4,5-b]pyridin-2-ylmethyl)-(5aR,5bS, 7aS, 8R, 10aS,10bS)-5,5a,5b6,7,7a,8,9,10,10a,10b,11,12,12a-tetradecahydro4H-imidazo[1,2-a]indeno[5,4-f]quinoline-8-carboxamide;N-[(4-phenyl-1H-imidazol-2-yl)methyl]-(5aR,5bS, 7aS, 8R, 10aS,10bS)-5,5a,5b6,7,7a,8,9,10,10a,10b,11,12,12a-tetradecahydro-4H-imidazo[1,2-a]indeno[5,4-f]quinoline-8-carboxamide;N-[(5-chloro-1H-benzoimidazol-2-yl)methyl]-(5aR,5bS, 7aS, 8R, 10aS,10bS)-5,5a,5b6,7,7a,8,9,10,10a,10b,11,12,12a-tetradecahydro4H-imidazo[1,2-a]indeno[5,4-f]quinoline-8-carboxamide;N-[(5-methoxy-1H-benzoimidazol-2-yl)methyl]-(5aR,5bS, 7aS, 8R, 10aS,10bS)-5,5a,5b6,7,7a,8,9,10,10a,10b,11,12,12a-tetradecahydro4H-imidazo[1,2-a]indeno[5,4-f]quinoline-8-carboxamide;pharmaceutically acceptable salts or stereoisomers thereof.
 3. Apharmaceutical composition comprising a compound of claim 1 or apharmaceutically acceptable salt or stereoisomer thereof and apharmaceutically acceptable carrier.
 4. A process for making apharmaceutical composition comprising combining a compound accordingclaim 1 or a pharmaceutically acceptable salt or stereoisomer thereofand a pharmaceutically acceptable carrier.
 5. A compound according toclaim 1, wherein R² is chosen from: hydrogen, hydroxyC₀₋₁₀alkyl,C₁₋₁₀alkyl, aryl C₀₋₁₀ alkyl, C₃₋₈ heterocyclyl C₀₋₁₀ alkyl, (C₀₋₁₀alkyl)₁₋₂aminocarbonyl-C₀₋₁₀ alkyl, C₃₋₈ heterocyclyl C₀₋₁₀ alkylaminocarbonyl C₀₋₁₀ alkyl, C₀₋₁₀ alkyl carbonylamino C₁₋₁₀ alkyl, C₀₋₁₀alkyloxy carbonyloxy C₀₋₁₀ alkyl, C₃₋₈ cycloalkyl C₀₋₁₀ alkyloxycarbonyloxy-C₀₋₁₀ alkyl, C₃₋₈ heterocyclyl C₀₋₁₀ alkyloxy-carbonyloxyC₀₋₁₀ alkyl, aryl C₀₋₁₀ alkyloxy carbonyloxy C₀₋₁₀ alkyl, C₁₋₁₀alkoxy-(carbonyl)₀₋₁C₀₋₁₀ alkyl, C₁₋₁₀alkyloxy-C₀₋₁₀alkyl, aryloxy C₀₋₁₀alkyl, C₃₋₈ cycloalkyloxy C₀₋₁₀-alkyl, C₃₋₈ heterocyclyloxy C₀₋₁₀ alkyl,C₃₋₈ heterocyclylC₀₋₁₀alkyloxy C₀₋₁₀ alkyl, and C₁₋₁₀ alkylcarbonyloxyC₀₋₁₀ alkyl; wherein in R², said aryl is selected from phenyl, naphthyl,indanyl, and tetrahydronapthyl, and said heterocyclyl is selected fromazabenzimidazolyl, benzimidazolyl, benzofuranyl, benzothiophenyl,benzoxazolyl, benzothiazolyl, benzodihydrofuranyl, 1,3-benzodioxolyl,2,3-dihydro-1,4-benzodioxinyl, imidazolyl, indanyl, indolyl, indazoyl,isoquinolyl, isothiazolyl, isoxazolyl, quinolyl, furanyl, thienyl,oxazolyl, thiazolyl, pyrazolyl, pyrrolyl, pyridyl, pyrimidyl, pyrazinyl,thiadiazolyl, oxadiazolyl, triazolyl, imidizopyridinyl, and tetrazolyl;and further wherein in R² is optionally substituted with one or moregroups, R³, chosen from halogen, aryl, C₁₋₈ alkyl, C₃₋₈ cycloalkyl, C₃₋₈cycloheteroalkyl, aryl-C₁₋₆ alkyl, amino-C₀₋₆ alkyl, C₁₋₆alkylamino-C₀₋₆ alkyl, (C₁₋₆ alkyl)2amino-C₀₋₆ alkyl, aryl-C₀₋₆alkylamino-C₀₋₆ alkyl, (aryl-C₀₋₆ alkyl)₂amino-C₀₋₆ alkyl, C₁₋₆alkylthio, aryl-C₀₋₆ alkylthio, C₁₋₆ alkylsulfinyl, aryl-C₀₋₆alkylsulfinyl, C₁₋₆ alkylsulfonyl, aryl-C₀₋₆ alkylsulfonyl, C₁₋₆alkoxy-C₀₋₆ alkyl, aryl-C₀₋₆ alkoxy-C₀₋₆ alkyl, hydroxycarbonyl-C₀₋₆alkyl, C₁₋₆ alkoxycarbonyl-C₀₋₆ alkyl, aryl-C₀₋₆ alkoxycarbonyl-C₀₋₆alkyl, hydroxycarbonyl-C₁₋₆ alkyloxy, hydroxy-C₀₋₆ alkyl, cyano, nitro,perfluoro-C₁₋₄ alkyl, perfluoro-C₁₋₄ alkoxy, C₁₋₆ alkylcarbonyloxy,aryl-C₀₋₆ alkylcarbonyloxy, C₁₋₆alkylcarbonylamino, aryl-C₀₋₆alkylcarbonylamino, C₁₋₆ alkylsulfonylamino, aryl-C₀₋₆alkylsulfonylamino, C₁₋₆ alkoxycarbonylamino, aryl-C₀₋₆alkoxycarbonylamino, C₁₋₆ alkylaminocarbonylamino, aryl-C₀₋₆ alkylamino-carbonylamino, (C₁₋₆ alkyl)₂ aminocarbonylamino, (aryl-C₀₋₆ alkyl)₂aminocarbonylamino, (C₁₋₆ alkyl)₂ aminocarbonyloxy, and (aryl-C₀₋₆alkyl)₂ aminocarbonyloxy; and wherein R³ is optionally substituted withone or more groups chosen from: OH, C₁₋₆ alkoxy, halogen, CO₂H, CN,O(C═O) C₁₋₆ alkyl, NO₂, trifluoromethoxy, trifluoroethoxy,—O(_(d))(C₁₋₁₀)perfluoroalkyl, and NH₂.
 6. A compound according to claim5, wherein R² is chosen from: hydroxyC₀₋₁₀alkyl, C₁₋₁₀ alkyl, aryl C₀₋₁₀alkyl, C₃₋₈ heterocyclyl C₀₋₁₀ alkyl, C₃₋₈ heterocyclyl C₀₋₁₀ alkyl-aminocarbonyl C₀₋₁₀ alkyl, C₀₋₁₀ alkyl carbonylamino C₁₋₁₀ alkyl, C₁₋₁₀alkoxy(carbonyl)₀₋₁C₀₋₁₀ alkyl, C₁₋₁₀alkyloxyC₀₋₁₀alkyl, aryloxy C₀₋₁₀alkyl, C₃₋₈ heterocyclyloxy C₀₋₁₀ alkyl, C₃₋₈ heterocyclylC₀₋₁₀alkyloxyC₀₋₁₀ alkyl, and C₁₋₁₀ alkylcarbonyloxy C₀₋₁₀ alkyl; wherein in R², saidaryl is selected from phenyl, naphthyl, indanyl, and tetrahydronapthyl,and said heterocyclyl is selected from azabenzimidazolyl,benzimidazolyl, benzofuranyl, benzothiophenyl, benzoxazolyl,benzothiazolyl, benzodihydrofuranyl, 1,3-benzodioxolyl,2,3-dihydro-1,4-benzodioxinyl, imidazolyl, indanyl, indolyl, indazoyl,isoquinolyl, isothiazolyl, isoxazolyl, quinolyl, furanyl, thienyl,oxazolyl, thiazolyl, pyrazolyl, pyrrolyl, pyridyl, pyrimidyl, pyrazinyl,thiadiazolyl, oxadiazolyl, triazolyl, imidizopyridinyl, and tetrazolyl.7. A compound according to claim 1, wherein a-b represents CH═CH.
 8. Acompound according to claim 1, wherein a-b represents CH₂CH₂.